Compositions and methods for inhibiting gene expression of lpa

ABSTRACT

RNA interference (RNAi) agents and RNAi agent conjugates for inhibiting the expression of the LPA (apo(a)) gene are described. Pharmaceutical compositions comprising one or more LPA RNAi agents optionally with one or more additional therapeutics are also described. Delivery of the described LPA RNAi agents to liver cells in vivo provides for inhibition of LPA gene expression and treatment of cardiovascular and cardiovascular-related diseases.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No. 15/901,810, filed Feb. 21, 2018. U.S. application Ser. No. 15/901,810, is a continuation of U.S. application Ser. No. 15/281,309, filed Sep. 30, 2016, now U.S. Pat. No. 9,932,586, which claims the benefit of U.S. Provisional Application No. 62/383,221, filed Sep. 2, 2016; U.S. Provisional Application No. 62/346,304, filed Jun. 6, 2016; and U.S. Provisional Application No. 62/235,816, filed Oct. 1, 2015, all of which are hereby incorporated by reference in their entireties.

DESCRIPTION OF THE TEXT FILE SUBMITTED ELECTRONICALLY

The present application contains a Sequence Listing, which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. The computer readable format copy of the Sequence Listing, which was created on May 6, 2020, is named A-2132-US-CNT2_SeqList.txt and is 610 kilobytes in size.

BACKGROUND

Lipoprotein(a) [Lp(a)] is a heterogeneous low density lipoprotein (LDL)-like particle containing a lipid core and apolipoprotein B (apoB-100) with a unique constituent, apolipoprotein (a) (apo(a)), that is attached to apoB-100 through a disulfide bond.

The apo(a) gene (LPA) is expressed predominantly in the liver and expression is restricted to human and non-human primates. Lp(a) levels in humans are genetically defined and do not change significantly with diet, exercise, or other lifestyle changes. LPA varies in length depending upon the number of Kringle KIV2 domains present and its expression is inversely correlated with the number of domains present. Normal Lp(a) levels range from 0.1-25 mg/d1, with about 25% of the population in the United States of America having Lp(a) levels of 30 mg/dl or higher.

Analysis of Lp(a) levels in multiple studies have implicated high Lp(a) levels as an independent risk factor for cardiovascular disease, stroke, and other related disorders including atherosclerotic stenosis. In addition, genome-wide association analyses have also implicated LPA as a genetic risk factor for diseases such as atherosclerotic stenosis.

When therapeutic lipoprotein apheresis is used to lower both Lp(a) and LDL levels in hyperlipidemic patients, significant reductions of cardiovascular events have been observed. Therefore there exists a need for therapeutics and treatments related to these and other LPA-related diseases.

SUMMARY

Described herein are LPA (also termed apo(a)) RNA interference (RNAi) agents (also termed RNAi trigger, or trigger) and compositions containing LPA RNAi agents for selectively and efficiently inhibiting expression of the LPA gene. LPA is the name of the gene which encodes apolipoprotein (a) (apo(a)), a key component of the lipoprotein (a) particle (Lp(a)). The LPA RNAi agents described herein can be used in the prevention or treatment or the preparation of a medicament for the prevention or treatment of diseases including, but not limited to: Berger's disease, peripheral artery disease, coronary artery disease, metabolic syndrome, acute coronary syndrome, aortic valve stenosis, aortic valve regurgitation, aortic dissection, retinal artery occlusion, cerebrovascular disease, mesenteric ischemia, superior mesenteric artery occlusion, renal artery stenosis, stable/unstable angina, acute coronary syndrome, heterozygous or homozygous familial hypercholesterolemia, hyperapobetalipoproteinemia, cerebrovascular atherosclerosis, cerebrovascular disease, and venous thrombosis.

Each LPA RNAi agent includes at least a sense strand and an antisense strand. The sense strand and the antisense strand can be partially, substantially, or fully complementary to each other. The length of the RNAi agent sense and antisense strands described herein each can be 17 to 30 nucleotides in length. In some embodiments, the sense and antisense strands are independently 17 to 26 nucleotides in length. The sense and antisense strands can be either the same length or different lengths. The RNAi agents described herein, upon delivery to a cell expressing the LPA gene, inhibit the expression of the LPA gene in vitro or in vivo.

A sense strand of an LPA RNAi agent comprises a nucleotide sequence having at least 90% identity over a core stretch of at least 17 consecutive nucleotides to a sequence in an LPA mRNA. In some embodiments, the sense strand nucleotide sequence having at least 90% identity to a sequence in the LPA mRNA is 17, 18, 19, 20, 21, 22, or 23 nucleotides in length. An antisense strand of an LPA RNAi agent comprises a nucleotide sequence having at least 90% complementary over a core stretch of at least 16 consecutive nucleotides to a sequence in the LPA mRNA and the corresponding sense strand. In some embodiments, the antisense strand nucleotide sequence having at least 90% complementarity to a sequence in the LPA mRNA or the corresponding sense strand is 17, 18, 19, 20, 21, 22, or 23 nucleotides in length.

In some embodiments, one or more LPA RNAi agents are delivered to target cells or tissues using any oligonucleotide delivery technology known in the art. Nucleic acid delivery methods include, but are not limited to, by encapsulation in liposomes, by iontophoresis, or by incorporation into other vehicles, such as hydrogels, cyclodextrins, biodegradable nanocapsules, and bioadhesive microspheres, proteinaceous vectors or Dynamic Polyconjugates™ (DPCs (see, for example WO 2000/053722, WO 2008/0022309, WO 2011/104169, and WO 2012/083185, each of which is incorporated herein by reference). In some embodiments, an LPA RNAi agent is conjugated to a targeting group. In some embodiments, the targeting group can include a cell receptor ligand, such as a galactose cluster, including a galactose cluster comprising an N-acetyl-galactosamine trimer.

In some embodiments are described pharmaceutical compositions comprising one or more LPA RNAi agents. In some embodiments, an LPA RNAi agent is optionally combined with one or more additional (i.e., second, third, etc.) therapeutics. An additional therapeutic can be another LPA RNAi agent (e.g., an LPA RNAi agent which targets a different sequence within the LPA target). An additional therapeutic can also be a small molecule drug, antibody, antibody fragment, and/or vaccine. The LPA RNAi agents, with or without the one or more additional therapeutics, can be combined with one or more excipients to form pharmaceutical compositions.

In some embodiments, compositions for delivering an LPA RNAi agent to a liver cell, particularly hepatocytes, in vivo are described, comprising: an LPA RNAi agent conjugated to a targeting group. In some embodiments, the targeting group is a asialoglycoprotein ligand.

Also described are methods of treating a human subject having a pathological state or at risk of developing a pathological state mediated at least in part by LPA expression, the methods comprising the step(s) of administering to the subject a therapeutically effective amount of an LPA RNAi agent or LPA RNAi agent-containing composition. The method of treating a subject with an LPA RNAi agent or LPA RNAi agent-containing composition can optionally be combined with one or more steps of administering one or more additional (i.e., second) therapeutics or treatments. The LPA RNAi agent and additional therapeutics can be administered in a single composition or they may be administered separately. Examples of additional therapeutics include, but are not limited to, HMg Co-A reductase inhibitors (statins), ezetimibe, PCSK-9 inhibitors, CTEP inhibitors, therapies targeting ANGPTL3, therapies targeting APOC3, and niacin.

Use of the described LPA RNAi agents can be used in methods for therapeutic prevention or treatment of diseases including, but not limited to: Berger's disease, peripheral artery disease, coronary artery disease, metabolic syndrome, acute coronary syndrome, aortic valve stenosis, aortic valve regurgitation, aortic dissection, retinal artery occlusion, cerebrovascular disease, mesenteric ischemia, superior mesenteric artery occlusion, renal artery stenosis, stable/unstable angina, acute coronary syndrome, heterozygous or homozygous familial hypercholesterolemia, hyperapobetalipoproteinemia, cerebrovascular atherosclerosis, cerebrovascular disease, and venous thrombosis. Such methods comprise administration of an LPA RNAi agent as described herein to a subject, e.g., a human or animal subject.

The pharmaceutical compositions can be administered in a number of ways depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration can be made by any way commonly known in the art, such as, but not limited to, topical (e.g., by a transdermal patch), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer, intratracheal, intranasal), epidermal, transdermal, oral or parenteral. Parenteral administration includes, but is not limited to, intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; subdermal (e.g., via an implanted device), intracranial, intraparenchymal, intrathecal, and intraventricular, administration. In some embodiments, the pharmaceutical compositions described herein are administered by subcutaneous injection.

The described LPA RNAi agents and/or compositions can be used in methods for therapeutic treatment of diseases, including but not limited to: Berger's disease, peripheral artery disease, coronary artery disease, metabolic syndrome, acute coronary syndrome, aortic valve stenosis, aortic valve regurgitation, aortic dissection, retinal artery occlusion, cerebrovascular disease, mesenteric ischemia, superior mesenteric artery occlusion, renal artery stenosis, stable/unstable angina, acute coronary syndrome, heterozygous or homozygous familial hypercholesterolemia, hyperapobetalipoproteinemia, cerebrovascular atherosclerosis, cerebrovascular disease, and venous thrombosis. Such methods comprise administration of an LPA RNAi agent as described herein to a subject, e.g., a human or animal subject.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

Other features and advantages of the invention will be apparent from the following detailed description, and from the claims.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1. Graph illustrating serum Lp(a) protein levels in Lp(a) transgenic (Tg) mice following a single subcutaneous administration of 0.5 mg/kg (dashed line) or 2 mg/kg (solid line) of indicated LPA RNAi agent. Lp(a) levels were normalized to day 1 and saline control.

FIG. 2. Graph illustrating serum Lp(a) protein levels in Lp(a) Tg mice following administration of three subcutaneous doses of 1 mg/kg (dashed line) or 3 mg/kg (solid line) of indicated LPA RNAi agent, administered once a week for three weeks (dose on days 1, 8, and 15). Lp(a) levels were normalized to day 1 and saline control.

FIG. 3. Graph illustrating Lp(a) particle levels in Cynomolgus monkey serum following administration of a single 2 mg/kg AD01196 LPA RNAi agent dosed 1:1 (wt/wt) with delivery polymer on day 1. Lp(a) levels were normalized to two pre-dose values (shown as day 0).

FIG. 4. Graph illustrating Lp(a) particle levels in Cynomolgus monkey serum following administration of 4 mg/kg or 6 mg/kg LPA RNAi agent dosed 1:1 (wt/wt) with delivery polymer on day 1 and day 71. Lp(a) levels were normalized to two pre-dose values (shown as day 0). 4 mg/kg dose=black circles; 6 mg/kg dose=gray squares.

FIG. 5. Graph illustrating Lp(a) particle levels in Cynomolgus monkey serum following three weekly subcutaneous doses of 3 mg/kg of AD02819 LPA RNAi agent on days 1, 8, and 15. Lp(a) levels were normalized to three pre-dose values (shown as day 0).

FIG. 6. Graph illustrating Lp(a) particle levels in Cynomolgus monkey serum following a single subcutaneous administration of 3 mg/kg of LPA RNAi agent on day 1. AD03460 and AD03536 groups received an additional 1 mg/kg dose of LPA RNAi agent on day 48. Lp(a) levels were normalized to three pre-dose values (shown as day 0).

DETAILED DESCRIPTION

Described herein are RNAi agents for inhibiting expression of the LPA gene (referred to herein as LPA RNAi agents). The RNAi agents described herein, upon delivery to a cell expressing the LPA gene, inhibit or knockdown expression of LPA in vitro and/or in vivo through the biological process of RNA interference (RNAi). As used herein, unless specifically noted otherwise, LPA may refer to an LPA gene, an LPA mRNA, or an LP(a) protein, as appropriate.

An LPA RNAi agent comprises a sense strand and an antisense strand. The sense strand and antisense strand each contain a core sequence 17-23 nucleobases in length. An antisense strand core sequence is 100% (perfectly) complementary or at least 90% (substantially) complementary to a nucleotide sequence (sometimes referred to, e.g., as a target sequence) present in an LPA mRNA. A sense strand core sequence is 100% (perfectly) complementary or at least 90% (substantially) complementary to a sequence in the antisense strand and thus the sense strand core sequence is perfectly identical or at least 90% identical to a nucleotide sequence (target sequence) present in the LPA mRNA. A sense strand core sequence can be the same length as a corresponding antisense core sequence or it can be a different length. In some embodiments, the antisense strand core sequence is 17, 18, 19, 20, 21, 22, or 23 nucleotides in length. In some embodiments, the sense strand core sequence is 17, 18, 19, 20, 21, 22, or 23 nucleotides in length.

LPA RNAi agent sense and antisense strands anneal to form a duplex. A sense strand and an antisense strand of an LPA RNAi agent are partially, substantially, or fully complementary to each other. Within the complementary duplex region, the sense strand core sequence is at least 90% complementary or 100% complementary to the antisense core sequence. In some embodiments, the sense strand core sequence contains a sequence of at least 17, at least 18, at least 19, at least 20, or at least 21 nucleotides that is at least 90% or 100% complementary to a corresponding 17, 18, 19, 20, or 21 nucleotide sequence of the antisense strand core sequence (i.e., the sense strand and antisense core sequences of an LPA RNAi agent have a region of at least 17, at least 18, at least 19, at least 20, or at least 21 nucleotides that is at least 90% base paired or 100% base paired.)

As used herein, and unless otherwise indicated, the term “complementary,” when used to describe a first nucleotide sequence (e.g., RNAi agent sense strand or LPA mRNA) in relation to a second nucleotide sequence (e.g., RNAi agent antisense strand), refers to the ability of an oligonucleotide or polynucleotide comprising the first nucleotide sequence to hybridize (form base pair hydrogen bonds) and form a duplex or double helical structure under certain conditions with an oligonucleotide or polynucleotide comprising the second nucleotide sequence. Complementary sequences include Watson-Crick base pairs or non-Watson-Crick base pairs and include natural or modified nucleotides or nucleotide mimics as long as the above requirements with respect to their ability to hybridize are fulfilled. “Perfectly complementary” or “fully complementary” means that all (100%) of the bases in a contiguous sequence of a first polynucleotide will hybridize with the same number of bases in a contiguous sequence of a second polynucleotide. The contiguous sequence may comprise all or a part of a first or second nucleotide sequence. As used herein, “partial complementary” means that in a hybridized pair of nucleobase sequences, at least 70% of the bases in a contiguous sequence of a first polynucleotide will hybridize with the same number of bases in a contiguous sequence of a second polynucleotide. As used herein, “substantial complementary” means that in a hybridized pair of nucleobase sequences, at least 85% of the bases in a contiguous sequence of a first polynucleotide will hybridize with the same number of bases in a contiguous sequence of a second polynucleotide. The terms “complementary”, “fully complementary” and “substantially complementary” as used herein may be used with respect to the base matching between the sense strand and the antisense strand of an RNAi agent, or between the antisense strand of an RNAi agent and a sequence of an LPA mRNA. Sequence identity or complementarity is independent of modification. For the purposes of determining identity or complementarity, for example, a and Af are complementary to U (or T) and identical to A.

The length of the LPA RNAi agent sense and antisense strands described herein are independently 17 to 30 nucleotides in length. In some embodiments, the sense and antisense strands are independently 17 to 26 nucleotides in length. In some embodiments, the sense and antisense strands are 19-26 nucleotides in length. In some embodiments, the described RNAi agent sense and antisense strands are independently 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26 nucleotides in length. The sense and antisense strands can be either the same length or they can be different lengths. In some embodiments, a sense strand and an antisense strand are each 26 nucleotides in length. In some embodiments, a sense strand is 23 nucleotides in length and an antisense strand is 21 nucleotides in length. In some embodiments, a sense strand is 22 nucleotides in length and an antisense strand is 21 nucleotides in length. In some embodiments, a sense strand is 21 nucleotides in length and an antisense strand is 21 nucleotides in length. In some embodiments, a sense strand is 19 nucleotides in length and an antisense strand is 21 nucleotides in length.

The sense strand and/or the antisense strand may optionally and independently contain an additional 1, 2, 3, 4, 5, or 6 nucleotides (extension) at the 3′ end, the 5′ end, or both the 3′ and 5′ ends of the core sequences. The antisense strand additional nucleotides, if present, may or may not be complementary to the corresponding sequence in the LPA mRNA. The sense strand additional nucleotides, if present, may or may not be identical to the corresponding sequence in the LPA mRNA. The antisense strand additional nucleotides, if present, may or may not be complementary to the corresponding sense strand's additional nucleotides, if present.

As used herein, an extension comprises 1, 2, 3, 4, 5, or 6 nucleotides at the 5′ and/or 3′ end of the sense strand core sequence and/or antisense strand core sequence. The extension nucleotides on a sense strand may or may not be complementary to nucleotides, either core sequence nucleotides or extension nucleotides, in the corresponding antisense strand. Conversely, the extension nucleotides on an antisense strand may or may not be complementary to nucleotides, either core sequence nucleotides or extension nucleotides, in the corresponding sense strand. In some embodiments, both the sense strand and the antisense strand of an RNAi agent contain 3′ and 5′ extensions. In some embodiments, one or more of the 3′ extension nucleotides of one strand base pairs with one or more 5′ extension nucleotides of the other strand. In other embodiments, one or more of 3′ extension nucleotides of one strand do not base pair with one or more 5′ extension nucleotides of the other strand. In some embodiments, an LPA RNAi agent has an antisense strand having a 3′ extension and a sense strand having a 5′ extension.

In some embodiments an LPA RNAi agent comprises an antisense strand having a 3′ extension of 1, 2, 3, 4, 5, or 6 nucleotides in length. In other embodiments, an LPA RNAi agent comprises an antisense strand having a 3′ extension of 1, 2, or 3 nucleotides in length. In some embodiments, one or more of the antisense strand extension nucleotides comprise uracil or thymidine nucleotides or nucleotides which are complementary to the corresponding LPA mRNA sequence. In some embodiments, a 3′ antisense strand extension includes or consists of, but is not limited to: Ab, AbAb, AUA, UGCUU, CUG, UG, UGCC, CUGCC, CGU, CUU, UGCCUA, CUGCCU, UGCCU, UGAUU, GCCUAU, T, TT (each listed 5′ to 3′).

In some embodiments, an LPA RNAi agent comprises an antisense strand having a 5′ extension of 1, 2, 3, 4, or 5 nucleotides in length. In other embodiments, an LPA RNAi agent comprises an antisense strand having a 5′ extension of 1 or 2 nucleotides in length. In some embodiments, one or more of the antisense strand extension nucleotides comprises uracil or thymidine nucleotides or nucleotides which are complementary to the corresponding LPA mRNA sequence. In some embodiments, the 5′ antisense strand extension includes or consists of, but is no limited to, UA, TU, U, T, CUC (each listed 5′ to 3′). An antisense strand may have any of the 3′ extensions described above in combination with any of the 5′ antisense strand extensions described, if present.

In some embodiments, an LPA RNAi agent comprises a sense strand having a 3′ extension of 1, 2, 3, 4, or 5 nucleotides in length. In some embodiments, one or more of the sense strand extension nucleotides comprises adenosine, uracil, or thymidine nucleotides, AT dinucleotide, or nucleotides which correspond to nucleotides in the LPA mRNA sequence. In some embodiments, the 3′ sense strand extension includes or consists of, but is no limited to: T, UUAb, UAb, Ab, UT, TT, UUT, TTT, or TTTT (each listed 5′ to 3′).

In some embodiments, an LPA RNAi agent comprises a sense strand having a 5′ extension of 1, 2, 3, 4, 5, or 6 nucleotides in length. In some embodiments, one or more of the sense strand extension nucleotides comprise uracil or adenosine nucleotides or nucleotides which correspond to nucleotides in the LPA mRNA sequence. In some embodiments, the sense strand 5′ extension can be, but is not limited to: CA, AUAGGC, AUAGG, AUAG, AUA, A, AA, AC, GCA, GGCA, GGC, UAUCA, UAUC, Ab, UCA, UAU (each listed 5′ to 3′). A sense strand may have a 3′ extension and/or a 5′ extension.

Examples of nucleotide sequences used in forming LPA RNAi agents are provided in Tables 1, 2A, 2B, 3A, and 3B. As used herein, the term “sequence” or “nucleotide sequence” refers to a succession or order of nucleobases, nucleotides, and/or nucleosides, whether modified or unmodified, described with a succession of letters using the standard nucleotide nomenclature and the key for modified nucleotides described herein.

RNAi agents include, but are not limited to: short interfering RNAs (siRNAs), double-strand RNAs (dsRNA), micro RNAs (miRNAs), short hairpin RNAs (shRNA), and dicer substrates (e.g., U.S. Pat. Nos. 8,084,599, 8,349,809, and 8,513,207).

Unmodified LPA RNAi agent sense strand and antisense strand sequences are provided in Table 1. In forming LPA RNAi agents, each of the nucleotides in each of the sequences listed in Table 1 may be a modified nucleotide.

TABLE 1 Unmodified LPA RNAi agent antisense strand and sense strand sequences. Antisense strand base SEQ Sense strand base SEQ sequence 5′→3′ ID NO. sequence 5′→3′ ID NO. TCGGCAGUCCCUUCUGCGUTT    1 ACGCAGAAGGGACUGCCGAT  190 TGUAGCACUCCUGCACCCCTT    2 GGGGUGCAGGAGUGCUACAT  191 TAAUAAGGGGCUGCCACAGTT    3 CUGUGGCAGCCCCUUAUUAT  192 TUAACAAUAAGGGGCUGCCTT    4 GGCAGCCCCUUAUUGUUAAT  193 TGUAUAACAAUAAGGGGCUTT    5 AGCCCCUUAUUGUUAUACAT  194 TCGUAUAACAAUAAGGGGCTT    6 GCCCCUUAUUGUUAUACGAT  195 TCGUCUGAGCAUUGUGUCATT    7 UGACACAAUGCUCAGACGAT  196 TGCGUCUGAGCAUUGUGUCTT    8 GACACAAUGCUCAGACGCAT  197 TUGCGUCUGAGCAUUGUGUTT    9 ACACAAUGCUCAGACGCAAT  198 TUCUGCGUCUGAGCAUUGUTT   10 ACAAUGCUCAGACGCAGAAT  199 TGGAUCUGGAUUUCGGCAGTT   11 CUGCCGAAAUCCAGAUCCAT  200 TCAGGAUCUGGAUUUCGGCTT   12 GCCGAAAUCCAGAUCCUGAT  201 TCAUCUGAGCAUCGUGUCATT   13 UGACACGAUGCUCAGAUGAT  202 TGCAUCUGAGCAUCGUGUCTT   14 GACACGAUGCUCAGAUGCAT  203 TUGCAUCUGAGCAUCGUGUTT   15 ACACGAUGCUCAGAUGCAAT  204 TUCUGCAUCUGAGCAUCGUTT   16 ACGAUGCUCAGAUGCAGAAT  205 TAAAGCCUCUAGGCUUGGATT   17 UCCAAGCCUAGAGGCUUUAT  206 TGUACCCCGGGGGUUUCCUTT   18 AGGAAACCCCCGGGGUACAT  207 TUGUACCCCGGGGGUUUCCTT   19 GGAAACCCCCGGGGUACAAT  208 TCUGUACCCCGGGGGUUUCTT   20 GAAACCCCCGGGGUACAGAT  209 TUCCAUAAUGGUAGUAGCATT   21 UGCUACUACCAUUAUGGAAT  210 TGUCCAUAAUGGUAGUAGCTT   22 GCUACUACCAUUAUGGACAT  211 TCUCUGUCCAUAAUGGUAGTT   23 CUACCAUUAUGGACAGAGAT  212 TCGACUAUGCUGGUGUGGUTT   24 ACCACACCAGCAUAGUCGAT  213 TCCGACUAUGCUGGUGUGGTT   25 CCACACCAGCAUAGUCGGAT  214 TUCCGACUAUGCUGGUGUGTT   26 CACACCAGCAUAGUCGGAAT  215 TGGUCCGACUAUGCUGGUGTT   27 CACCAGCAUAGUCGGACCAT  216 TUUUCUGGGGUCCGACUAUTT   28 AUAGUCGGACCCCAGAAAAT  217 TUUUUCUGGGGUCCGACUATT   29 UAGUCGGACCCCAGAAAAAT  218 TGCGAAUCUCAGCAUCUGGTT   30 CCAGAUGCUGAGAUUCGCAT  219 TCCAAGGGCGAAUCUCAGCTT   31 GCUGAGAUUCGCCCUUGGAT  220 TACCAAGGGCGAAUCUCAGTT   32 CUGAGAUUCGCCCUUGGUAT  221 TCACCAAGGGCGAAUCUCATT   33 UGAGAUUCGCCCUUGGUGAT  222 TACACCAAGGGCGAAUCUCTT   34 GAGAUUCGCCCUUGGUGUAT  223 TCCUGACACUGGGAUCCAUTT   35 AUGGAUCCCAGUGUCAGGAT  224 TUGCAAGGACACUUGAUUCTT   36 GAAUCAAGUGUCCUUGCAAT  225 TUUGCAAGGACACUUGAUUTT   37 AAUCAAGUGUCCUUGCAAAT  226 TUUGCUCCGUUGGUGCUUCTT   38 GAAGCACCAACGGAGCAAAT  227 TAAUGAGCCUCGAUAACUCTT   39 GAGUUAUCGAGGCUCAUUAT  228 TGAAUGAGCCUCGAUAACUTT   40 AGUUAUCGAGGCUCAUUCAT  229 TGGAUAAUAUUCUGUUGUCTT   41 GACAACAGAAUAUUAUCCAT  230 TCCAUGGUAUAACACCAAGTT   42 CUUGGUGUUAUACCAUGGAT  231 TGAUCCAUGGUAUAACACCTT   43 GGUGUUAUACCAUGGAUCAT  232 TAUUGGGAUCCAUGGUAUATT   44 UAUACCAUGGAUCCCAAUAT  233 TCAUUGGGAUCCAUGGUAUTT   45 AUACCAUGGAUCCCAAUGAT  234 TACAUUGGGAUCCAUGGUATT   46 UACCAUGGAUCCCAAUGUAT  235 TGACAUUGGGAUCCAUGGUTT   47 ACCAUGGAUCCCAAUGUCAT  236 TGACAUUGUGUCAGGUUGCTT   48 GCAACCUGACACAAUGUCAT  237 TCACUGGACAUUGUGUCAGTT   49 CUGACACAAUGUCCAGUGAT  238 TACUUGAUUCUGUCACUGGTT   50 CCAGUGACAGAAUCAAGUAT  239 TGAGAAUGAGCCUCGAUAATT   51 UUAUCGAGGCUCAUUCUCAT  240 TCCAUUUGGGUAGUAUUCUTT   52 AGAAUACUACCCAAAUGGAT  241 TCACCAUUUGGGUAGUAUUTT   53 AAUACUACCCAAAUGGUGAT  242 TCCACCAUUUGGGUAGUAUTT   54 AUACUACCCAAAUGGUGGAT  243 TAUAACACCAAGGGCGAAUTT   55 AUUCGCCCUUGGUGUUAUAT  244 TACUGGGAUCCAUGGUAUATT   56 UAUACCAUGGAUCCCAGUAT  245 TCACUGGGAUCCAUGGUAUTT   57 AUACCAUGGAUCCCAGUGAT  246 TACCACCGUGGGAGUUGUGTT   58 CACAACUCCCACGGUGGUAT  247 TCAAGACUGACAUGUUCUUTT   59 AAGAACAUGUCAGUCUUGAT  248 TGGGAGUUGUGAGGACACUTT   60 AGUGUCCUCACAACUCCCAT  249 TUCUCAGGUGGUGCUUGUUTT   61 AACAAGCACCACCUGAGAAT  250 TCACAGGGCUUUUCUCAGGTT   62 CCUGAGAAAAGCCCUGUGAT  251 TGAUGCCAGUGUGGUAUCATT   63 UGAUACCACACUGGCAUCAT  252 TUGAUGCCAGUGUGGUAUCTT   64 GAUACCACACUGGCAUCAAT  253 TGACACCUGAUUCUGUUUCTT   65 GAAACAGAAUCAGGUGUCAT  254 TGGACACCUGAUUCUGUUUTT   66 AAACAGAAUCAGGUGUCCAT  255 TCUAGGACACCUGAUUCUGTT   67 CAGAAUCAGGUGUCCUAGAT  256 TAUAAGGGGCUGCCACAGGTT   68 CCUGUGGCAGCCCCUUAUAT  257 TAACAAUAAGGGGCUGCCATT   69 UGGCAGCCCCUUAUUGUUAT  258 TGUCCGACUAUGCUGGUGUTT   70 ACACCAGCAUAGUCGGACAT  259 TUCUCAGCAUCUGGAUUCCTT   71 GGAAUCCAGAUGCUGAGAAT  260 TCGAAUCUCAGCAUCUGGATT   72 UCCAGAUGCUGAGAUUCGAT  261 TAAGGGCGAAUCUCAGCAUTT   73 AUGCUGAGAUUCGCCCUUAT  262 TUGACACUGGGAUCCAUGGTT   74 CCAUGGAUCCCAGUGUCAAT  263 TCCGUUGGUGCUUCUUCAGTT   75 CUGAAGAAGCACCAACGGAT  264 TCUUGAUUCUGUCACUGGATT   76 UCCAGUGACAGAAUCAAGAT  265 TCACCGUGGGAGUUGUGAGTT   77 CUCACAACUCCCACGGUGAT  266 TUCUAGGACACCUGAUUCUTT   78 AGAAUCAGGUGUCCUAGAAT  267 TAGUCUCUAGGACACCUGATT   79 UCAGGUGUCCUAGAGACUAT  268 TCAAUAAGGGGCUGCCACATT   80 UAUAGCCCCUUAUUGUUAUACAT  269 TCUGCGUCUGAGCAUUGUGTT   81 UAUGCCCCUUAUUGUUAUACGAT  270 TACAGGAUCUGGAUUUCGGTT   82 UAUGACACAAUGCUCAGACGCAT  271 TCCGGGGGUUUCCUCAGUCTT   83 UAUACACAAUGCUCAGACGCAAT  272 TUGUCCAUAAUGGUAGUAGTT   84 UAUUUAUCGAGGCUCAUUCUCAT  273 TUCUGUCCAUAAUGGUAGUTT   85 UAUGAAACAGAAUCAGGUGUCAT  274 TACUCUGUCCAUAAUGGUATT   86 UAUACACCAGCAUAGUCGGACAT  275 TAACUCUGUCCAUAAUGGUTT   87 UAUUCCAGAUGCUGAGAUUCGAT  276 TGGGCGAAUCUCAGCAUCUTT   88 UAUAUGCUGAGAUUCGCCCUUAT  277 TAGGGCGAAUCUCAGCAUCTT   89 UAUCCAUGGAUCCCAGUGUCAAT  278 TAACACCAAGGGCGAAUCUTT   90 UGUGGCAGCCCCUUAUUGAT  279 TAGGACACUUGAUUCUGUCTT   91 CACAAUGCUCAGACGCAGAT  280 TGGACCAAGACUGACAUGUTT   92 CCGAAAUCCAGAUCCUGUAT  281 TGGUCAGGCCACCAUUUGGTT   93 GACUGAGGAAACCCCCGGAT  282 TAUCCAUGGUAUAACACCATT   94 CUACUACCAUUAUGGACAAT  283 TGGGAUCCAUGGUAUAACATT   95 ACUACCAUUAUGGACAGAAT  284 TUGGACAUUGUGUCAGGUUTT   96 UACCAUUAUGGACAGAGUAT  285 TAUUCUGUCACUGGACAUUTT   97 ACCAUUAUGGACAGAGUUAT  286 TGGUGCUUGUUCAGAAACATT   98 AGAUGCUGAGAUUCGCCCAT  287 TGGAGAAUGAGCCUCGAUATT   99 GAUGCUGAGAUUCGCCCUAT  288 TGUGGAGAAUGAGCCUCGATT  100 AGAUUCGCCCUUGGUGUUAT  289 TCCGUGGGAGUUGUGAGGATT  101 GACAGAAUCAAGUGUCCUAT  290 TGGACCACCGUGGGAGUUGTT  102 ACAUGUCAGUCUUGGUCCAT  291 TUGCUUGUUCAGAAGGAGCTT  103 CCAAAUGGUGGCCUGACCAT  292 TCUGAUGCCAGUGUGGUAUTT  104 UGGUGUUAUACCAUGGAUAT  293 TUAGGACACCUGAUUCUGUTT  105 UGUUAUACCAUGGAUCCCAT  294 TCUCUAGGACACCUGAUUCTT  106 AACCUGACACAAUGUCCAAT  295 TUCUCUAGGACACCUGAUUTT  107 AAUGUCCAGUGACAGAAUAT  296 TGUCUCUAGGACACCUGAUTT  108 UGUUUCUGAACAAGCACCAT  297 TGAGAAUGAGCCUCGAUAACUCUUAU  109 UAUCGAGGCUCAUUCUCCAT  298 TGACACCUGAUUCUGUUUCUGAGUAU  110 UCGAGGCUCAUUCUCCACAT  299 TCGUAUAACAAUAAGGGGCUGCCUAU  111 UCCUCACAACUCCCACGGAT  300 TGCGUCUGAGCAUUGUGUCAGGUUAU  112 CAACUCCCACGGUGGUCCAT  301 TUGCGUCUGAGCAUUGUGUCAGGUAU  113 GCUCCUUCUGAACAAGCAAT  302 TAAGGGCGAAUCUCAGCAUCUGGUAU  114 AUACCACACUGGCAUCAGAT  303 UUAACAAUAAGGGGCUGCAb  115 ACAGAAUCAGGUGUCCUAAT  304 UGUAUAACAAUAAGGGGCAb  116 GAAUCAGGUGUCCUAGAGAT  305 UCGUAUAACAAUAAGGGGAb  117 AAUCAGGUGUCCUAGAGAAT  306 UGCGUCUGAGCAUUGUGUAb  118 AUCAGGUGUCCUAGAGACAT  307 UUGCGUCUGAGCAUUGUGAb  119 UAUAUAGUUAUCGAGGCUCAUUCUCA  308 UCAGGAUCUGGAUUUCGGAb  120 UAUAUCAGAAACAGAAUCAGGUGUCA  309 UUGCAUCUGAGCAUCGUGAb  121 UAUAUCAGCCCCUUAUUGUUAUACGA  310 UCGACUAUGCUGGUGUGGAb  122 UAUAUCUGACACAAUGCUCAGACGCA  311 UUUUCUGGGGUCCGACUAAb  123 UAUAUUGACACAAUGCUCAGACGCAA  312 UGCGAAUCUCAGCAUCUGAb  124 UAUAUAGAUGCUGAGAUUCGCCCUUA  313 UUGCAAGGACACUUGAUUAb  125 GCAGCCCCUUAUUGUUAA  314 UAAUGAGCCUCGAUAACUAb  126 GCCCCUUAUUGUUAUACA  315 UGAAUGAGCCUCGAUAACAb  127 CCCCUUAUUGUUAUACGA  316 UGACAUUGUGUCAGGUUGAb  128 ACACAAUGCUCAGACGCA  317 UGAGAAUGAGCCUCGAUAAb  129 CACAAUGCUCAGACGCAA  318 UCCAUUUGGGUAGUAUUCAb  130 CCGAAAUCCAGAUCCUGA  319 UCACCAUUUGGGUAGUAUAb  131 CACGAUGCUCAGAUGCAA  320 UGACACCUGAUUCUGUUUAb  132 CCACACCAGCAUAGUCGA  321 UGGACACCUGAUUCUGUUAb  133 UAGUCGGACCCCAGAAAA  322 UUAACAAUAAGGGGCUGAbAb  134 CAGAUGCUGAGAUUCGCA  323 UGUAUAACAAUAAGGGGAbAb  135 AAUCAAGUGUCCUUGCAA  324 UCGUAUAACAAUAAGGGAbAb  136 AGUUAUCGAGGCUCAUUA  325 UGCGUCUGAGCAUUGUGAbAb  137 GUUAUCGAGGCUCAUUCA  326 UUGCGUCUGAGCAUUGUAbAb  138 CAACCUGACACAAUGUCA  327 UCAGGAUCUGGAUUUCGAbAb  139 UAUCGAGGCUCAUUCUCA  328 UUGCAUCUGAGCAUCGUAbAb  140 GAAUACUACCCAAAUGGA  329 UCGACUAUGCUGGUGUGAbAb  141 AUACUACCCAAAUGGUGA  330 UUUUCUGGGGUCCGACUAbAb  142 AAACAGAAUCAGGUGUCA  331 UGCGAAUCUCAGCAUCUAbAb  143 AACAGAAUCAGGUGUCCA  332 UUGCAAGGACACUUGAUAbAb  144 CAGCCCCUUAUUGUUAA  333 UAAUGAGCCUCGAUAACAbAb  145 CCCCUUAUUGUUAUACA  334 UGAAUGAGCCUCGAUAAAbAb  146 CCCUUAUUGUUAUACGA  335 UGACAUUGUGUCAGGUUAbAb  147 CACAAUGCUCAGACGCA  336 UGAGAAUGAGCCUCGAUAbAb  148 ACAAUGCUCAGACGCAA  337 UCCAUUUGGGUAGUAUUAbAb  149 CGAAAUCCAGAUCCUGA  338 UCACCAUUUGGGUAGUAAbAb  150 ACGAUGCUCAGAUGCAA  339 UGACACCUGAUUCUGUUAbAb  151 CACACCAGCAUAGUCGA  340 UGGACACCUGAUUCUGUAbAb  152 AGUCGGACCCCAGAAAA  341 UGAGAAUGAGCCUCGAUAACUCUUAU  153 AGAUGCUGAGAUUCGCA  342 UGACACCUGAUUCUGUUUCUGAGUAU  154 AUCAAGUGUCCUUGCAA  343 UGAGAAUGAGCCUCGAUAACUCTUAU  155 GUUAUCGAGGCUCAUUA  344 UCGUAUAACAAUAAGGGGCUGCCUAU  156 UUAUCGAGGCUCAUUCA  345 UGAGAAUGAGCCUCGAUAATT  157 AACCUGACACAAUGUCA  346 UCGUAUAACAAUAAGGCGCUGCCUAU  158 AUCGAGGCUCAUUCUCA  347 UGAGAAUGAGCCUCGATAbAb  159 AAUACUACCCAAAUGGA  348 UGACACCUGAUUCUGTTAbAb  160 UACUACCCAAAUGGUGA  349 UCGUAUAACAAUAAGGGGCUGAUU  161 AACAGAAUCAGGUGUCA  350 UCGUAUAACAAUAAGGGGCUGCUU  162 ACAGAAUCAGGUGUCCA  351 UGAGAAUGAGCCUCGAUAACUCUU  163 UAUAUCAGCGCCUUAUUGUUAUACGA  352 UCGUAUAACAAUAAGGGGCUU  164 ATCGAGGCUCAUUCUCA  353 UGUAUAACAAUAAGGGG  165 UCAGCCCCUUAUUGUUAUACGAUUAb  354 UCGUAUAACAAUAAGGG  166 UcAGccccuuAuuGuuAuAcGAAb  355 UGAGAAUGAGCCUCGAT  167 UAGUUAUCGAGGCUCAUUCUCAUUAb  356 UGACACCUGAUUCUGTT  168 AbGCCCCUUAUUGUUAUACGAUUAb  357 TUCGUAUAACAAUAAGGGGCUGCCUA  169 AUAUCAGCCCCUUAUUGUUAUACGAT  358 UAUCGUAUAACAAUAAGGGGCUGCCU  170 UAUCAGCCCCUUAUUGUUAUACGAUT  359 TCCGUAUAACAAUAAGGGGCUGCCUA  171 AUAUAGUUAUCGAGGCUCAUUCUCAT  360 CUCCGUAUAACAAUAAGGGGCUGCCU  172 UAUAGUUAUCGAGGCUCAUUCUCAUT  361 TUGAGAAUGAGCCUCGAUAACUCUUA  173 AbUUAUCGAGGCUCAUUCUCAUUAb  362 UAUGAGAAUGAGCCUCGAUAACUCUU  174 UAUAUAAUUAUCGAGGCUCAUUCUCAAb  363 TGGAGAAUGAGCCUCGAUAACUCUUA  175 GGCAGCCCCUUAUUGUUAUACGATT  364 GUGGAGAAUGAGCCUCGAUAACUCUU  176 GGCAGCCCCUUAUUGUUAUACGAUUT  365 UGAGAAUGAGCCUCGAUAAUU  177 CAGCCCCUUAUUGUUAUACGATTTT  366 TCGUAUAACAAUAAGGGGCUU  178 GCGAUAGUUAUCGAGGCUCAUUCUCA  367 UGAGAAUGAGCCUCGAUAAUUAUAUA  179 UGAAUAGUUAUCGAGGCUCAUUCUCA  368 UCGUAUAACAAUAAGGGGCUGCC  180 AUCGUAGUUAUCGAGGCUCAUUCUCA  369 TUCGUAUAACAAUAAGGGGCUGCC  181 UAUAAAGUUAUCGAGGCUCAUUCUCA  370 TUCGUAUAACAAUAAGGGGCUG  182 AGCCCCUUAUUGUUAUACGAAb  371 UGAGAAUGAGCCUCGAUAACUAUCGC  183 AAGCCCCUUAUUGUUAUACGAAb  372 UGAGAAUGAGCCUCGAUAACUAUUCA  184 GCAGCCCCUUAUUGUUAUACGAAb  373 UGAGAAUGAGCCUCGAUAACUACGAU  185 UAUAUAGUUAUCGAGGCUCAUUCUCAAb  374 UCGUAUAACAAUAAGGGGCGU  186 ACGCCCCUUAUUGUUAUACGAAb  375 UCGUAUAACAAUAAGGGGCUGCCU  187 GccccuuAuuGuuAuAcGAuuAb  376 UCGUAUAACAAUAAGGGGCUG  188 AGCCCCUUAUUGUUAUACGAUUAb  377 TCGUAUAACAAUAAGGGGCUGCUU  189 AAGccccuuAuuGuuAuAcGAuuAb  378 TCGUAUAACAAUAAGGGGC 1242 UAUCAGCCCCUUAUUGUUAUACGA  379 UCGUAUAACAAUAAGGGG 1244 UAGCAGCCCCUUAUUGUUAUACGA  380 UCGUAUAACAAUAAGGG 1246 GCAGCCCCUUAUUGUUAUACGA  381 TGAGAAUGAGCCUCGAUAA 1248 AUAAGAGUUAUCGAGGCUCAUUCUCA  382 UGAGAAUGAGCCUCGAUA 1250 AUAGGCAGCCCCUUAUUGUUAUACGA  383 UGAGAAUGAGCCUCGAU 1252 CAGCCCCUUAUUGUUAUACGA  384 UGUAUAACAAUAAGGGG 1254 UAUAUCAGCCCCTUAUUGUUAUACGA  385 CGUAUAACAAUAAGGGGC 1280 AbGCCCCTUAUUGUUAUACGAUUAb 1241 GAGAAUGAGCCUCGAUAA 1281 GCCCCUUAUUGUUAUACGA 1243 UCGUAUAACAAUAAGGGGC 1282 CCCCUUAUUGUUAUACGA 1245 UGAGAAUGAGCCUCGAUAA 1283 CCCUUAUUGUUAUACGA 1247 UUAUCGAGGCUCAUUCUCA 1249 UAUCGAGGCUCAUUCUCA 1251 AUCGAGGCUCAUUCUCA 1253 CCCCUUAUUGUUAUACA 1255 UUAUCGAGGCUCAUUCUCA 1258 GCCCCUUAUUGUUAUACGA 1259 ACAGCCCCUUAUUGUUAUACGA 1260 AAAGCCCCUUAUUGUUAUACGA 1261 GCCCCUUAUUGUUAUACG 1284 UUAUCGAGGCUCAUUCUC 1285 Ab = abasic nucleotide

The LPA RNAi agents described herein are formed by annealing an antisense strand with a sense strand. A sense strand containing a sequence listed in Table 1 or Table 2B can be hybridized to any antisense strand containing a sequence listed in Table 1 or Table 2A provided the two sequences have a region of at least 90% complementarity over a contiguous 16, 17, 18, 19, 20, or 21 nucleotide sequence.

In some embodiments, an LPA RNAi agent antisense strand comprises a nucleotide sequence of any of the sequences in Table 1. In some embodiments, an LPA RNAi agent antisense strand comprises the sequence of nucleotides 1-17, 2-17, 1-18, 2-18, 1-19, 2-19, 1-20, 2-20, 1-21, 2-21, 1-22, 2-22, 1-23, 2-23, 1-24, 2-24, 1-25, 2-25, 1-26, or 2-26 of any of the sequences in Table 1. In some embodiments, an LPA RNAi agent sense strand comprises the nucleotide sequence of any of the sequences in Tables 1. In some embodiments, an LPA RNAi agent sense strand comprises the sequence of nucleotides 1-17, 2-17, 1-18, 2-18, 1-19, 2-19, 1-20, 2-20, 1-21, 2-21, 1-22, 2-22, 1-23, 2-23, 1-24, 2-24, 1-25, 2-25, 1-26, or 2-26 of any of the sequences in Table 1.

In some embodiments, the sense and antisense strands of the RNAi agents described herein contain the same number of nucleotides. In some embodiments the sense and antisense strands of the RNAi agents described herein contain different numbers of nucleotides. In some embodiments, the sense strand 5′ end and the antisense strand 3′ end of an RNAi agent form a blunt end. In some embodiments, the sense strand 3′ end and the antisense strand 5′ end of an RNAi agent form a blunt end. In some embodiments, both ends of an RNAi agent form blunt ends. In some embodiments, neither end of an RNAi agent is blunt-ended. As used herein a blunt end refers to an end of a double stranded RNAi agent in which the terminal nucleotides of the two annealed strands are complementary (form a complementary base-pair). In some embodiments, the sense strand 5′ end and the antisense strand 3′ end of an RNAi agent form a frayed end. In some embodiments, the sense strand 3′ end and the antisense strand 5′ end of an RNAi agent form a frayed end. In some embodiments, both ends of an RNAi agent form a frayed end. In some embodiments, neither end of an RNAi agent is a frayed end. As used herein a frayed end refers to an end of a double stranded RNAi agent in which the terminal nucleotides of the two annealed strands from a pair (i.e. do not form an overhang) but are not complementary (i.e. form a non-complementary pair). As used herein, an overhang is a stretch of one or more unpaired nucleotides at the end of one strand of a double stranded RNAi agent.

The unpaired nucleotides may be on the sense strand or the antisense strand, creating either 3′ or 5′ overhangs. In some embodiments the RNAi agent contains: a blunt end and a frayed end, a blunt end and 5′ overhang end, a blunt end and a 3′ overhang end, a frayed end and a 5′ overhang end, a frayed end and a 3′ overhang end, two 5′ overhang ends, two 3′ overhang ends, a 5′ overhang end and a 3′ overhang end, two frayed ends, or two blunt ends.

A nucleotide base (or nucleobase) is a heterocyclic pyrimidine or purine compound which is a constituent of all nucleic acids and includes adenine (A), guanine (G), cytosine (C), thymine (T), and uracil (U). As used herein, the term “nucleotide” can include a modified nucleotide or nucleotide mimic, abasic site (Ab or X), or a surrogate replacement moiety.

In some embodiments, an LPA RNAi agent is prepared or provided as a salt, mixed salt, or a free-acid.

Modified Nucleotides

In some embodiments, an LPA RNAi agent contains one or more modified nucleotides. As used herein, a “modified nucleotide” is a nucleotide other than a ribonucleotide (2′-hydroxyl nucleotide). In some embodiments, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% of the nucleotides are modified. Modified nucleotides include, but are not limited to, deoxynucleotides, nucleotide mimics, abasic nucleotides (represented herein as X, Ab), 2′-modified nucleotides, 3′ to 3′ linkages (inverted) nucleotides (represented herein as invdN, invN, invn, invX, invAb, non-natural base-comprising nucleotides, bridged nucleotides, peptide nucleic acids (PNAs), 2′,3′-seco nucleotide mimics (unlocked nucleobase analogues, represented herein as N_(UNA) or NUNA), locked nucleotides (represented herein as N_(LNA) or NLNA), 3′-O-Methoxy (2′ internucleoside linked) nucleotides (represented herein as 3′-OMen), 2′-F-Arabino nucleotides (represented herein as NfANA or Nf_(ANA)), 5′-Me,2′-fluoro nucleotide (represented herein as 5Me-Ne, morpholino nucleotides, vinyl phosphonate deoxyribonucleotides (represented herein as vpdN), vinyl phosphonate containing nucleotides, and cyclopropyl phosphonate containing nucleotides (cPrpN). 2′-modified nucleotides (i.e. a nucleotide with a group other than a hydroxyl group at the 2′ position of the five-membered sugar ring) include, but are not limited to, 2′-O-methyl nucleotides (represented herein as a lower case letter ‘n’ in a nucleotide sequence), 2′-deoxy-2′-fluoro nucleotides (represented herein as Nf, also represented herein as 2′-fluoro nucleotide), 2′-deoxy nucleotides (represented herein as dN), 2′-methoxyethyl (2′-O-2-methoxylethyl) nucleotides (represented herein as NM or 2′-MOE), 2′-amino nucleotides, and 2′-alkyl nucleotides. It is not necessary for all positions in a given compound to be uniformly modified. Conversely, more than one modification may be incorporated in a single LPA RNAi agent or even in a single nucleotide thereof. The LPA RNAi agent sense strands and antisense strands may be synthesized and/or modified by methods known in the art. Modification at one nucleotide is independent of modification at another nucleotide.

Modified nucleotides also include nucleotides having modified nucleobases. Modified nucleobases include, but are not limited to, synthetic and natural nucleobases, 5-substituted pyrimidines, 6-azapyrimidines and N-2, N-6 and 0-6 substituted purines, including 2-aminopropyladenine, 5-propynyluracil and 5-propynylcytosine, 5-methylcytosine (5-me-C), 5-hydroxymethyl cytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-methyl and other alkyl derivatives of adenine and guanine, 2-propyl and other alkyl derivatives of adenine and guanine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-halouracil and cytosine, 5-propynyl uracil and cytosine, 6-azo uracil, cytosine and thymine, 5-uracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxyl and other 8-substituted adenines and guanines, 5-halo particularly 5-bromo, 5-trifluoromethyl and other 5-substituted uracils and cytosines, 7-methylguanine and 7-methyladenine, 8-azaguanine and 8-azaadenine, 7-deazaguanine and 7-deazaadenine and 3-deazaguanine and 3-deazaadenine.

Modified Internucleoside Linkages

In some embodiments, one or more nucleotides of an LPA RNAi agent are linked by non-standard linkages or backbones (i.e. modified internucleoside linkages or modified backbones). In some embodiments, a modified internucleoside linkage is a non-phosphate-containing covalent internucleoside linkage. Modified internucleoside linkages or backbones include, but are not limited to, 5′-phosphorothioate group (represented herein as a lower case ‘s’ before a nucleotide, as in sN, sn, sNf, or sdN), chiral phosphorothioates, thiophosphate, phosphorodithioates, phosphotriesters, aminoalkyl-phosphotriesters, methyl and other alkyl phosphonates including 3′-alkylene phosphonates and chiral phosphonates, phosphinates, phosphoramidates including 3′-amino phosphoramidate and aminoalkylphosphoramidates, thionophosphoramidates, thionoalkyl-phosphonates, thionoalkylphosphotriesters, morpholino linkages, and boranophosphates having normal 3′-5′ linkages, 2′-5′ linked analogs of these, and those having inverted polarity wherein the adjacent pairs of nucleoside units are linked 3′-5′ to 5′-3′ or 2′-5′ to 5′-2′. In other embodiments, a modified internucleoside linkage or backbone lacks a phosphorus atom. Modified internucleoside linkages lacking a phosphorus atom include, but are not limited to, short chain alkyl or cycloalkyl inter-sugar linkages, mixed heteroatom and alkyl or cycloalkyl inter-sugar linkages, or one or more short chain heteroatomic or heterocyclic inter-sugar linkages. In some embodiments, modified internucleoside backbones include, but are not limited to, siloxane backbones, sulfide, sulfoxide and sulfone backbones; formacetyl and thioformacetyl backbones, methylene formacetyl and thioformacetyl backbones, alkene containing backbones, sulfamate backbones, methyleneimino and methylenehydrazino backbones, sulfonate and sulfonamide backbones, amide backbones; and others having mixed N, O, S, and CH₂ component parts.

In some embodiments, a sense strand of an LPA RNAi agent can contain 1, 2, 3, 4 phosphorothioate linkages, an antisense strand of an LPA RNAi agent can contain 1, 2, 3, or 4 phosphorothioate linkages, or both the sense strand and the antisense strand independently can contain 1, 2, 3, or 4 phosphorothioate linkages.

In some embodiments, an LPA RNAi agent sense strand contains two phosphorothioate internucleoside linkages. In some embodiments, the two phosphorothioate internucleoside linkages are between the nucleotides at positions 1-3 from the 3′ end of the sense strand. In some embodiments, the two phosphorothioate internucleoside linkages are between the nucleotides at positions 1-3, 2-4, 3-5, 4-6, 4-5, or 6-8 from the 5′ end of the sense strand. In some embodiments, an LPA RNAi agent antisense strand contains four phosphorothioate internucleoside linkages. In some embodiments, the four phosphorothioate internucleoside linkages are between the nucleotides at positions 1-3 from the 5′ end of the sense strand and between the nucleotides at positions 19-21, 20-22, 21-23, 22-24, 23-25, or 24-26 from the 5′ end. In some embodiments, an LPA RNAi agent contains two phosphorothioate internucleoside linkages in the sense strand and four phosphorothioate internucleoside linkages in the antisense strand.

In some embodiments, an LPA RNAi agent contains one or more modified nucleotides and one or more modified internucleoside linkages. In some embodiments, a 2′-modified nucleotide is combined with modified internucleoside linkage.

LPA RNAi Agents Having Modified Nucleotides

Examples of antisense strands containing modified nucleotides are provided in Table 2A. Examples of sense strands containing modified nucleotides are provided in Table 2B. In Tables 2A and 2B, the following notations are used to indicate modified nucleotides:

-   -   N=2′-OH (unmodified) ribonucleotide (capital letter without f or         d indication)     -   n=2′-OMe modified nucleotide     -   Nf=2′-fluoro modified nucleotide     -   dN=2′-deoxy nucleotides     -   NUNA=2′,3′-seco nucleotide mimics (unlocked nucleobase analogs)     -   NINA=locked nucleotide     -   NfANA=2′-F-Arabino nucleotide     -   NM=2′-methoxyethyl nucleotide     -   Ab=abasic ribose     -   (invdN)=inverted deoxyribonucleotide (3′-3′ linked nucleotide)     -   (invAb)=inverted abasic nucleotide     -   (invn)=inverted 2′-OMe nucleotide     -   s=phosphorothioate linked nucleotide     -   p=phosphate     -   vpdN=vinyl phosphonate deoxyribonucleotide     -   (3′OMen)=3′-OMe nucleotide     -   (5Me-Nf)=5′-Me, 2′-fluoro nucleotide     -   cPrp=cyclopropyl phosphonate     -   epTcPr=see Table 4     -   epTM=see Table 4

In addition the following targeting groups and linking groups are listed in Tables 2A and 2B: (Alk-PEG5-C6), (C11-PEG5-NAG5), (C12), (C6-PEG4-NAG3), (C6-SS-Alk-Me), (Chol-TEG), (Dy540), (NAG13), (NAG18), (NAG24), (NAG25), (NAG26), (NAG27), (NAG28), (NAG29), (NAG30), (NAG31), (NAG32), (NAG33), (NAG34), (NAG35), (NAG36), (NAG37), (NAG4), (PAZ), (Sp18), (Steryl), (Alk-SMPT-C6). Each sense strand and/or antisense strand can have any of the above indicated targeting groups or linking groups, as well as other targeting or linking groups, conjugated to the 5′ and or 3′ end of the sequence. The chemical structures for these groups are provided in Table 4.

TABLE 2A LPA RNAi agent antisense strands having modified nucleotides. Antisense SEQ SEQ Strand ID Antisense strand sequence 5′→3′ ID NO. ID NO. AM01240-AS dTCfgGfcAfgUfcCfcUfuCfuGfcGfudTsdT  386   1 AM01241-AS dTGfuAfgCfaCfuCfcUfgCfaCfcCfcdTsdT  387   2 AM01242-AS dTAfaUfaAfgGfgGfcUfgCfcAfcAfgdTsdT  388   3 AM01243-AS dTUfaAfcAfaUfaAfgGfgGfcUfgCfcdTsdT  389   4 AM01244-AS dTGfuAfuAfaCfaAfuAfaGfgGfgCfudTsdT  390   5 AM01245-AS dTCfgUfaUfaAfcAfaUfaAfgGfgGfcdTsdT  391   6 AM01246-AS dTCfgUfcUfgAfgCfaUfuGfuGfuCfadTsdT  392   7 AM01247-AS dTGfcGfuCfuGfaGfcAfuUfgUfgUfcdTsdT  393   8 AM01248-AS dTUfgCfgUfcUfgAfgCfaUfuGfuGfudTsdT  394   9 AM01249-AS dTUfcUfgCfgUfcUfgAfgCfaUfuGfudTsdT  395  10 AM01250-AS dTGfgAfuCfuGfgAfuUfuCfgGfcAfgdTsdT  396  11 AM01251-AS dTCfaGfgAfuCfuGfgAfuUfuCfgGfcdTsdT  397  12 AM01252-AS dTCfaUfcUfgAfgCfaUfcGfuGfuCfadTsdT  398  13 AM01253-AS dTGfcAfuCfuGfaGfcAfuCfgUfgUfcdTsdT  399  14 AM01254-AS dTUfgCfaUfcUfgAfgCfaUfcGfuGfudTsdT  400  15 AM01255-AS dTUfcUfgCfaUfcUfgAfgCfaUfcGfudTsdT  401  16 AM01256-AS dTAfaAfgCfcUfcUfaGfgCfuUfgGfadTsdT  402  17 AM01257-AS dTGfuAfcCfcCfgGfgGfgUfuUfcCfudTsdT  403  18 AM01258-AS dTUfgUfaCfcCfcGfgGfgGfuUfuCfcdTsdT  404  19 AM01259-AS dTCfuGfuAfcCfcCfgGfgGfgUfuUfcdTsdT  405  20 AM01260-AS dTUfcCfaUfaAfuGfgUfaGfuAfgCfadTsdT  406  21 AM01261-AS dTGfuCfcAfuAfaUfgGfuAfgUfaGfcdTsdT  407  22 AM01262-AS dTCfuCfuGfuCfcAfuAfaUfgGfuAfgdTsdT  408  23 AM01263-AS dTCfgAfcUfaUfgCfuGfgUfgUfgGfudTsdT  409  24 AM01264-AS dTCfcGfaCfuAfuGfcUfgGfuGfuGfgdTsdT  410  25 AM01265-AS dTUfcCfgAfcUfaUfgCfuGfgUfgUfgdTsdT  411  26 AM01266-AS dTGfgUfcCfgAfcUfaUfgCfuGfgUfgdTsdT  412  27 AM01267-AS dTUfuUfcUfgGfgGfuCfcGfaCfuAfudTsdT  413  28 AM01268-AS dTUfuUfuCfuGfgGfgUfcCfgAfcUfadTsdT  414  29 AM01269-AS dTGfcGfaAfuCfuCfaGfcAfuCfuGfgdTsdT  415  30 AM01270-AS dTCfcAfaGfgGfcGfaAfuCfuCfaGfcdTsdT  416  31 AM01271-AS dTAfcCfaAfgGfgCfgAfaUfcUfcAfgdTsdT  417  32 AM01272-AS dTCfaCfcAfaGfgGfcGfaAfuCfuCfadTsdT  418  33 AM01273-AS dTAfcAfcCfaAfgGfgCfgAfaUfcUfcdTsdT  419  34 AM01274-AS dTCfcUfgAfcAfcUfgGfgAfuCfcAfudTsdT  420  35 AM01275-AS dTUfgCfaAfgGfaCfaCfuUfgAfuUfcdTsdT  421  36 AM01276-AS dTUfuGfcAfaGfgAfcAfcUfuGfaUfudTsdT  422  37 AM01277-AS dTUfuGfcUfcCfgUfuGfgUfgCfuUfcdTsdT  423  38 AM01278-AS dTAfaUfgAfgCfcUfcGfaUfaAfcUfcdTsdT  424  39 AM01279-AS dTGfaAfuGfaGfcCfuCfgAfuAfaCfudTsdT  425  40 AM01280-AS dTGfgAfuAfaUfaUfuCfuGfuUfgUfcdTsdT  426  41 AM01281-AS dTCfcAfuGfgUfaUfaAfcAfcCfaAfgdTsdT  427  42 AM01282-AS dTGfaUfcCfaUfgGfuAfuAfaCfaCfcdTsdT  428  43 AM01283-AS dTAfuUfgGfgAfuCfcAfuGfgUfaUfadTsdT  429  44 AM01284-AS dTCfaUfuGfgGfaUfcCfaUfgGfuAfudTsdT  430  45 AM01285-AS dTAfcAfuUfgGfgAfuCfcAfuGfgUfadTsdT  431  46 AM01286-AS dTGfaCfaUfuGfgGfaUfcCfaUfgGfudTsdT  432  47 AM01287-AS dTGfaCfaUfuGfuGfuCfaGfgUfuGfcdTsdT  433  48 AM01288-AS dTCfaCfuGfgAfcAfuUfgUfgUfcAfgdTsdT  434  49 AM01289-AS dTAfcUfuGfaUfuCfuGfuCfaCfuGfgdTsdT  435  50 AM01290-AS dTGfaGfaAfuGfaGfcCfuCfgAfuAfadTsdT  436  51 AM01291-AS dTCfcAfuUfuGfgGfuAfgUfaUfuCfudTsdT  437  52 AM01292-AS dTCfaCfcAfuUfuGfgGfuAfgUfaUfudTsdT  438  53 AM01293-AS dTCfcAfcCfaUfuUfgGfgUfaGfuAfudTsdT  439  54 AM01294-AS dTAfuAfaCfaCfcAfaGfgGfcGfaAfudTsdT  440  55 AM01295-AS dTAfcUfgGfgAfuCfcAfuGfgUfaUfadTsdT  441  56 AM01296-AS dTCfaCfuGfgGfaUfcCfaUfgGfuAfudTsdT  442  57 AM01297-AS dTAfcCfaCfcGfuGfgGfaGfuUfgUfgdTsdT  443  58 AM01298-AS dTCfaAfgAfcUfgAfcAfuGfuUfcUfudTsdT  444  59 AM01299-AS dTGfgGfaGfuUfgUfgAfgGfaCfaCfudTsdT  445  60 AM01300-AS dTUfcUfcAfgGfuGfgUfgCfuUfgUfudTsdT  446  61 AM01301-AS dTCfaCfaGfgGfcUfuUfuCfuCfaGfgdTsdT  447  62 AM01302-AS dTGfaUfgCfcAfgUfgUfgGfuAfuCfadTsdT  448  63 AM01303-AS dTUfgAfuGfcCfaGfuGfuGfgUfaUfcdTsdT  449  64 AM01304-AS dTGfaCfaCfcUfgAfuUfcUfgUfuUfcdTsdT  450  65 AM01305-AS dTGfgAfcAfcCfuGfaUfuCfuGfuUfudTsdT  451  66 AM01306-AS dTCfuAfgGfaCfaCfcUfgAfuUfcUfgdTsdT  452  67 AM01796-AS dTAfuAfaGfgGfgCfuGfcCfaCfaGfgdTsdT  453  68 AM01798-AS dTAfaCfaAfuAfaGfgGfgCfuGfcCfadTsdT  454  69 AM01800-AS dTGfuCfcGfaCfuAfuGfcUfgGfuGfudTsdT  455  70 AM01802-AS dTUfcUfcAfgCfaUfcUfgGfaUfuCfcdTsdT  456  71 AM01804-AS dTCfgAfaUfcUfcAfgCfaUfcUfgGfadTsdT  457  72 AM01806-AS dTAfaGfgGfcGfaAfuCfuCfaGfcAfudTsdT  458  73 AM01808-AS dTUfgAfcAfcUfgGfgAfuCfcAfuGfgdTsdT  459  74 AM01810-AS dTCfcGfuUfgGfuGfcUfuCfuUfcAfgdTsdT  460  75 AM01812-AS dTCfuUfgAfuUfcUfgUfcAfcUfgGfadTsdT  461  76 AM01814-AS dTCfaCfcGfuGfgGfaGfuUfgUfgAfgdTsdT  462  77 AM01816-AS dTUfcUfaGfgAfcAfcCfuGfaUfuCfudTsdT  463  78 AM01818-AS dTAfgUfcUfcUfaGfgAfcAfcCfuGfadTsdT  464  79 AM02003-AS dTGfuAfuAfaCfaAfuaaGfgGfgCfudTsdT  465 5 AM02004-AS dTGfuAfuA_(UNA)aCfaAfuaaGfgGfgCfudTsdT  466 5 AM02005-AS dTGfuAfuAfA_(UNA)CfaAfuaaGfgGfgCfudTsdT  467 5 AM02007-AS dTCfgUfaUfaAfcAfauaAfgGfgGfcdTsdT  468 6 AM02008-AS dTCfgUfaU_(UNA)aAfcAfauaAfgGfgGfcdTsdT  469 6 AM02009-AS dTCfgUfaUfA_(UNA)AfcAfauaAfgGfgGfcdTsdT  470 6 AM02011-AS dTGfcGfuCfuGfaGfcauUfgUfgUfcdTsdT  471 8 AM02012-AS dTGfcGfuC_(UNA)uGfaGfcauUfgUfgUfcdTsdT  472 8 AM02013-AS dTGfcGfuCfU_(UNA)GfaGfcauUfgUfgUfcdTsdT  473 8 AM02015-AS dTUfgCfgUfcUfgAfgcaUfuGfuGfudTsdT  474 9 AM02016-AS dTUfgCfgU_(UNA)cUfgAfgcaUfuGfuGfudTsdT  475 9 AM02017-AS dTUfgCfgUfC_(UNA)UfgAfgcaUfuGfuGfudTsdT  476 9 AM02019-AS dTGfaGfaAfuGfaGfccuCfgAfuAfadTsdT  477  51 AM02020-AS dTGfaGfaA_(UNA)uGfaGfccuCfgAfuAfadTsdT  478  51 AM02021-AS dTGfaGfaAfU_(UNA)GfaGfccuCfgAfuAfadTsdT  479  51 AM02023-AS dTGfaCfaCfcUfgAfuucUfgUfuUfcdTsdT  480  65 AM02024-AS dTGfaCfaC_(UNA)cUfgAfuucUfgUfuUfcdTsdT  481  65 AM02025-AS dTGfaCfaCfC_(UNA)UfgAfuucUfgUfuUfcdTsdT  482  65 AM02027-AS dTGfuCfcGfaCfuAfugcUfgGfuGfudTsdT  483  70 AM02028-AS dTGfuCfcG_(UNA)aCfuAfugcUfgGfuGfudTsdT  484  70 AM02029-AS dTGfuCfcGfA_(UNA)CfuAfugcUfgGfuGfudTsdT  485  70 AM02031-AS dTCfgAfaUfcUfcAfgcaUfcUfgGfadTsdT  486  72 AM02032-AS dTCfgAfaU_(UNA)cUfcAfgcaUfcUfgGfadTsdT  487  72 AM02033-AS dTCfgAfaUfC_(UNA)UfcAfgcaUfcUfgGfadTsdT  488  72 AM02035-AS dTAfaGfgGfcGfaAfucuCfaGfcAfudTsdT  489  73 AM02036-AS dTAfaGfgG_(UNA)cGfaAfucuCfaGfcAfudTsdT  490  73 AM02037-AS dTAfaGfgGfC_(UNA)GfaAfucuCfaGfcAfudTsdT  491  73 AM02039-AS dTUfgAfcAfcUfgGfgauCfcAfuGfgdTsdT  492  74 AM02040-AS dTUfgAfcA_(UNA)cUfgGfgauCfcAfuGfgdTsdT  493  74 AM02041-AS dTUfgAfcAfC_(UNA)UfgGfgauCfcAfuGfgdTsdT  494  74 AM02240-AS dTCfaAfuAfaGfgGfgcuGfcCfaCfadTsdT  495  80 AM02241-AS dTCfuGfcGfuCfuGfagcAfuUfgUfgdTsdT  496  81 AM02242-AS dTAfcAfgGfaUfcUfggaUfuUfcGfgdTsdT  497  82 AM02243-AS dTCfcGfgGfgGfuUfuccUfcAfgUfcdTsdT  498  83 AM02244-AS dTUfgUfcCfaUfaAfuggUfaGfuAfgdTsdT  499  84 AM02245-AS dTUfcUfgUfcCfaUfaauGfgUfaGfudTsdT  500  85 AM02246-AS dTAfcUfcUfgUfcCfauaAfuGfgUfadTsdT  501  86 AM02247-AS dTAfaCfuCfuGfuCfcauAfaUfgGfudTsdT  502  87 AM02248-AS dTGfgGfcGfaAfuCfucaGfcAfuCfudTsdT  503  88 AM02249-AS dTAfgGfgCfgAfaUfcucAfgCfaUfcdTsdT  504  89 AM02250-AS dTAfaCfaCfcAfaGfggcGfaAfuCfudTsdT  505  90 AM02251-AS dTAfgGfaCfaCfuUfgauUfcUfgUfcdTsdT  506  91 AM02252-AS dTGfgAfcCfaAfgAfcugAfcAfuGfudTsdT  507  92 AM02253-AS dTGfgUfcAfgGfcCfaccAfuUfuGfgdTsdT  508  93 AM02254-AS dTAfuCfcAfuGfgUfauaAfcAfcCfadTsdT  509  94 AM02255-AS dTGfgGfaUfcCfaUfgguAfuAfaCfadTsdT  510  95 AM02256-AS dTUfgGfaCfaUfuGfuguCfaGfgUfudTsdT  511  96 AM02257-AS dTAfuUfcUfgUfcAfcugGfaCfaUfudTsdT  512  97 AM02258-AS dTGfgUfgCfuUfgUfucaGfaAfaCfadTsdT  513  98 AM02259-AS dTGfgAfgAfaUfgAfgccUfcGfaUfadTsdT  514  99 AM02260-AS dTGfuGfgAfgAfaUfgagCfcUfcGfadTsdT  515 100 AM02261-AS dTCfcGfuGfgGfaGfuugUfgAfgGfadTsdT  516 101 AM02262-AS dTGfgAfcCfaCfcGfuggGfaGfuUfgdTsdT  517 102 AM02263-AS dTUfgCfuUfgUfuCfagaAfgGfaGfcdTsdT  518 103 AM02264-AS dTCfuGfaUfgCfcAfgugUfgGfuAfudTsdT  519 104 AM02265-AS dTUfaGfgAfcAfcCfugaUfuCfuGfudTsdT  520 105 AM02266-AS dTCfuCfuAfgGfaCfaccUfgAfuUfcdTsdT  521 106 AM02267-AS dTUfcUfcUfaGfgAfcacCfuGfaUfudTsdT  522 107 AM02268-AS dTGfuCfuCfuAfgGfacaCfcUfgAfudTsdT  523 108 AM02404-AS dTsGfsaGfaAfuGfaGfcCfuCfgAfuAfaCfuCfsusuAu  524 109 AM02406-AS dTsGfsaGfaAfuGfaGfccUfCfgAfuAfaCfuCfsusuAu  525 109 AM02408-AS dTsGfsaGfaAfuGfaGfccUfcgAfuAfaCfuCfsusuAu  526 109 AM02410-AS dTsGfsaGfaAfuGfaGfcCfUfcGfaUfaAfcUfcsUfsuAu  527 109 AM02412-AS dTsGfsaCfaCfcUfgAfuUfcUfgUfuUfcUfgAfsgsuAu  528 110 AM02414-AS dTsGfsaCfaCfcUfgAfuuCfUfgUfuUfcUfgAfsgsuAu  529 110 AM02416-AS dTsGfsaCfaCfcUfgAfuuCfugUfuUfcUfgAfsgsuAu  530 110 AM02418-AS dTsGfsaCfaCfcUfgAfuUfCfuGfuUfuCfuGfasGfsuAu  531 110 AM02531-AS dTsCfsgUfaUfaAfcAfauaAfgGfgGfcUfgCfscsuAu  532 111 AM02532-AS dTsGfscGfuCfuGfaGfcauUfgUfgUfcAfgGfsusuAu  533 112 AM02533-AS dTsUfsgCfgUfcUfgAfgcaUfuGfuGfuCfaGfsgsuAu  534 113 AM02534-AS dTsGfsaGfaAfuGfaGfccuCfgAfuAfaCfuCfsusuAu  535 109 1532-AS00 AM02535-AS dTsGfsaCfaCfcUfgAfuucUfgUfuUfcUfgAfsgsuAu  536 110 1533-AS00 AM02536-AS dTsAfsaGfgGfcGfaAfucuCfaGfcAfuCfuGfsgsuAu  537 114 AM02755-AS usUfsaAfcAfaUfaAfgGfgGfcUfgCfAbs(PAZ)  538 115 AM02756-AS usGfsuAfuAfaCfaAfuAfaGfgGfgCfAbs(PAZ)  539 116 AM02757-AS usCfsgUfaUfaAfcAfaUfaAfgGfgGfAbs(PAZ)  540 117 AM02758-AS usGfscGfuCfuGfaGfcAfuUfgUfgUfAbs(PAZ)  541 118 AM02759-AS usUfsgCfgUfcUfgAfgCfaUfuGfuGfAbs(PAZ)  542 119 AM02760-AS usCfsaGfgAfuCfuGfgAfuUfuCfgGfAbs(PAZ)  543 120 AM02761-AS usUfsgCfaUfcUfgAfgCfaUfcGfuGfAbs(PAZ)  544 121 AM02762-AS usCfsgAfcUfaUfgCfuGfgUfgUfgGfAbs(PAZ)  545 122 AM02763-AS usUfsuUfcUfgGfgGfuCfcGfaCfuAfAbs(PAZ)  546 123 AM02764-AS usGfscGfaAfuCfuCfaGfcAfuCfuGfAbs(PAZ)  547 124 AM02765-AS usUfsgCfaAfgGfaCfaCfuUfgAfuUfAbs(PAZ)  548 125 AM02766-AS usAfsaUfgAfgCfcUfcGfaUfaAfcUfAbs(PAZ)  549 126 AM02767-AS usGfsaAfuGfaGfcCfuCfgAfuAfaCfAbs(PAZ)  550 127 AM02768-AS usGfsaCfaUfuGfuGfuCfaGfgUfuGfAbs(PAZ)  551 128 AM02769-AS usGfsaGfaAfuGfaGfcCfuCfgAfuAfAbs(PAZ)  552 129 AM02770-AS usCfscAfuUfuGfgGfuAfgUfaUfuCfAbs(PAZ)  553 130 AM02771-AS usCfsaCfcAfuUfuGfgGfuAfgUfaUfAbs(PAZ)  554 131 AM02772-AS usGfsaCfaCfcUfgAfuUfcUfgUfuUfAbs(PAZ)  555 132 AM02773-AS usGfsgAfcAfcCfuGfaUfuCfuGfuUfAbs(PAZ)  556 133 AM02774-AS usUfsaAfcAfaUfaAfgGfgGfcUfgAbAbs(PAZ)  557 134 AM02775-AS usGfsuAfuAfaCfaAfuAfaGfgGfgAbAbs(PAZ)  558 135 AM02776-AS usCfsgUfaUfaAfcAfaUfaAfgGfgAbAbs(PAZ)  559 136 AM02777-AS usGfscGfuCfuGfaGfcAfuUfgUfgAbAbs(PAZ)  560 137 AM02778-AS usUfsgCfgUfcUfgAfgCfaUfuGfuAbAbs(PAZ)  561 138 AM02779-AS usCfsaGfgAfuCfuGfgAfuUfuCfgAbAbs(PAZ)  562 139 AM02780-AS usUfsgCfaUfcUfgAfgCfaUfcGfuAbAbs(PAZ)  563 140 AM02781-AS usCfsgAfcUfaUfgCfuGfgUfgUfgAbAbs(PAZ)  564 141 AM02782-AS usUfsuUfcUfgGfgGfuCfcGfaCfuAbAbs(PAZ)  565 142 AM02783-AS usGfscGfaAfuCfuCfaGfcAfuCfuAbAbs(PAZ)  566 143 AM02784-AS usUfsgCfaAfgGfaCfaCfuUfgAfuAbAbs(PAZ)  567 144 AM02785-AS usAfsaUfgAfgCfcUfcGfaUfaAfcAbAbs(PAZ)  568 145 AM02786-AS usGfsaAfuGfaGfcCfuCfgAfuAfaAbAbs(PAZ)  569 146 AM02787-AS usGfsaCfaUfuGfuGfuCfaGfgUfuAbAbs(PAZ)  570 147 AM02788-AS usGfsaGfaAfuGfaGfcCfuCfgAfuAbAbs(PAZ)  571 148 AM02789-AS usCfscAfuUfuGfgGfuAfgUfaUfuAbAbs(PAZ)  572 149 AM02790-AS usCfsaCfcAfuUfuGfgGfuAfgUfaAbAbs(PAZ)  573 150 AM02791-AS usGfsaCfaCfcUfgAfuUfcUfgUfuAbAbs(PAZ)  574 151 AM02792-AS usGfsgAfcAfcCfuGfaUfuCfuGfuAbAbs(PAZ)  575 152 AM02857-AS usGfsaGfaAfuGfaGfccuCfgAfuAfaCfuCfsusuAu  576 153 1532-AS14 AM02858-AS usgsaGfaAfuGfaGfccuCfgAfuAfaCfuCfsusuAu  577 153 AM02859-AS usgsaGfaAfuGfaGfccuCfgAfuAfaCfucsusuAu  578 153 AM02860-AS usGfsaGfaAfuGfaGfccuCfgAfuAfaCfucsusuAu  579 153 AM02863-AS usGfsaCfaCfcUfgAfuucUfgUfuUfcUfgAfsgsuAu  580 154 1533-AS15 AM02864-AS usgsaCfaCfcUfgAfuucUfgUfuUfcUfgAfsgsuAu  581 154 AM02865-AS usgsaCfaCfcUfgAfuucUfgUfuUfcUfgasgsuAu  582 154 AM02866-AS usGfsaCfaCfcUfgAfuucUfgUfuUfcUfgasgsuAu  583 154 AM02943-AS usgsagaAfugaGfccuCfgAfuaaCfuCfsusuAu  584 153 AM02944-AS usgsagaauGfagccuCfgauAfaCfuCfsusuAu  585 153 AM02945-AS usgsagaauGfagccuCfgauAfacucsusuAu  586 153 AM02950-AS usgsaCfaCfcUfgAfuucUfgUfuucUfgasgsuAu  587 154 AM02951-AS usgsaCfaCfcUfgAfuucUfguuUfcugasgsuAu  588 154 AM02952-AS usgsacaccugAfuucUfgUfuucUfgasgsuAu  589 154 AM03040-AS usGfsAfcAfcCfUfgAfuucUfgUfuUfcUfgAfsgsuAu  590 154 AM03041-AS usGfsAfcAfccUfgAfuucUfgUfuUfcUfgAfsgsuAu  591 154 AM03043-AS usGfsaCfaCfCfUfgAfuucUfgUfuUfcUfgAfsgsuAu  592 154 AM03065-AS dTsGfsaCfaCfcugauucUfgUfuUfcUfgAfsgsuAu  593 110 1533-AS18 AM03066-AS usGfsaCfaCfcugauucUfgUfuUfcUfgAfsgsuAu  594 154 1533-AS03 AM03067-AS dTsGfsaCfaCfcugauucUfgUfuucugasgsuAu  595 110 AM03068-AS usGfsaCfaCfcugauucUfgUfuucugasgsuAu  596 154 AM03069-AS dTsGfsaCfaCfcUfgAfuucUfgUfuucugasgsuAu  597 110 1533-AS14 AM03070-AS usGfsaCfaCfcUfgAfuucUfgUfuucugasgsuAu  598 154 1533-AS29 AM03107-AS usCfsgUfaUfaAfcAfauaAfgGfgGfcUfgCfscsuAu  599 156 AM03108-AS usCfsgUfaUfaAfcAfauaAfgGfgGfcUfgcscsuAu  600 156 AM03119-AS usGfsaGfaAfuGfaGfccuCfgAfuAfaCfuCMsTMsuAu  601 155 AM03120-AS usGfsaGfaAfuGfaGfccuCfgAfuAfaCfuCMTMuAu  602 155 AM03121-AS usGfsaGfaAfuGfaGfccuCfgAfuAfaCfucuuAu  603 153 AM03127-AS usCfsgUfaUfaAfCfAfauaAfgGfgGfcUfgCfscsuAu  604 156 AM03129-AS usCfsgUfaUfaAfCfAfauaAfgGfgGfcUfgcscsuAu  605 156 AM03130-AS usGfsaGfaAfuGfaGfCfcuCfgAfuAfaCfuCfsusuAu  606 153 AM03131-AS usGfsaGfaAfuGfaGfCfCfuCfgAfuAfaCfuCfsusuAu  607 153 AM03149-AS usGfsagaAfugaGfccuCfgAfuaaCfuCfsusuAu  608 153 AM03150-AS usGfsagaauGfagccuCfgauAfaCfuCfsusuAu  609 153 AM03151-AS usGfsagaauGfagccuCfgauAfacucsusuAu  610 153 AM03255-AS 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usCfsgUfaUfaacaaUfaAfgGfgGfcUfgCfsusu  781 162 AM04823-AS vpusCfsgUfaUfaacaaUfaAfgGfgGfcUfgCfscsu  782 187 AM04824-AS vpusCfsgUfaUfaacaaUfaAfgGfgGfcUfgCfsusu  783 162 AM04871-AS usGfsaGfaAfuGfAfgccuCfgAfuAfaCfusCfsuuAu  784 153 AM04872-AS cPrpusGfsaGfaAfuGfaGfccuCfgAfuAfaCfucsusuAu  785 153 AM04873-AS cPrpusCfsgUfaUfaacaaUfaAfgGfgGfcUfgCfscsuAu  786 156 AM04874-AS usCfsgUfaUfaacaaUfaAfgGfgGfcsusu  787 164 AM04875-AS cPrpusCfsgUfaUfaacaaUfaAfgGfgGfcsusu  788 164 AM04876-AS usCfsgUfaUfaacaaUfaAfgGfgGfcsusg  789 188 AM04877-AS usCfsgUfaUfaacaaUfaAfgGfgGfcsUfsg  790 188 AM04878-AS cPrpusCfsgUfaUfaacaaUfaAfgGfgGfcUfgCfsusu  791 162 AM04879-AS usGfsaGfaAfuGfaGfcCfuCfgAfuAfaCfucsusuAu  792 153 AM04880-AS cPrpusGfsaGfaAfuGfaGfcCfuCfgAfuAfaCfucsusuAu  793 153 AM04969-AS cPrpTMsGfsaGfaAfuGfaGfcCfuCfgAfuAfaCfucsusuAu  794 109 AM04970-AS cPrpTMsCfsgUfaUfaacaaUfaAfgGfgGfcUfgCfscsuAu  795 111 AM04971-AS cPrpTMsCfsgUfaUfaacaaUfaAfgGfgGfcsusu  796 178 AM04972-AS cPrpTMsCfsgUfaUfaacaaUfaAfgGfgGfcUfgCfsusu  797 189 AM04979-AS usCfsgsUfaUfaAfcAfaUfaAfgGfgGfcusu  798 164 1532-AS01 usgsagaaugaGfccuCfgAfuAfaCfuCfsusuAu  799 153 1532-AS02 usgsagaauGfagccuCfgAfuAfaCfuCfsusuAu  800 153 1532-AS03 usgsagaAfugagccuCfgAfuAfaCfuCfsusuAu  801 153 1532-AS04 usgsaGfaaugagccuCfgAfuAfaCfuCfsusuAu  802 153 1532-AS05 usGfsagaaugagccuCfgAfuAfaCfuCfsusuAu  803 153 1532-AS06 dTsgsagaaugagccuCfgAfuAfaCfuCfsusuAu  804 109 1532-AS07 dTsGfsaGfaAfugagccuCfgAfuAfaCfuCfsusuAu  805 109 1532-AS08 dTsGfsaGfaAfugaGfccuCfgauAfaCfuCfsusuAu  806 109 1532-AS09 dTsGfsaGfaAfuGfagccuCfgauAfaCfuCfsusuAu  807 109 1532-AS10 dTsGfsaGfaAfugagccuCfgauAfaCfuCfsusuAu  808 109 1532-AS11 dTsGfsaGfaAfugagccuCfgAfuaaCfuCfsusuAu  809 109 1532-AS12 dTsGfsaGfaAfugaGfccuCfgauaaCfuCfsusuAu  810 109 1532-AS13 dTsGfsaGfaAfuGfagccuCfgauaaCfuCfsusuAu  811 109 1532-AS15 dTsgsagaaugaGfccuCfgAfuAfaCfuCfsusuAu  812 109 1532-AS16 dTsgsagaauGfagccuCfgAfuAfaCfuCfsusuAu  813 109 1532-AS17 dTsgsagaAfugagccuCfgAfuAfaCfuCfsusuAu  814 109 1532-AS18 dTsgsaGfaaugagccuCfgAfuAfaCfuCfsusuAu  815 109 1532-AS19 dTsGfsagaaugagccuCfgAfuAfaCfuCfsusuAu  816 109 1532-AS20 usgsagaaugagccuCfgAfuAfaCfuCfsusuAu  817 153 1532-AS21 usGfsaGfaAfugagccuCfgAfuAfaCfuCfsusuAu  818 153 1532-AS22 usGfsaGfaAfugaGfccuCfgauAfaCfuCfsusuAu  819 153 1532-AS23 usGfsaGfaAfuGfagccuCfgauAfaCfuCfsusuAu  820 153 1532-AS24 usGfsaGfaAfugagccuCfgauAfaCfuCfsusuAu  821 153 1532-AS25 usGfsaGfaAfugagccuCfgAfuaaCfuCfsusuAu  822 153 1532-AS27 usGfsaGfaAfuGfagccuCfgauaaCfuCfsusuAu  823 153 1533-AS01 usgsaCfaCfcugAfuucUfgUfuUfcUfgAfsgsuAu  824 154 1533-AS02 usgsaCfaCfcUfgauucUfgUfuUfcUfgAfsgsuAu  825 154 1533-AS04 dTsgsaCfaCfcugauucUfgUfuUfcUfgAfsgsuAu  826 110 1533-AS05 dTsGfsaCfaCfcugAfuucUfguuUfcUfgAfsgsuAu  827 110 1533-AS06 dTsGfsaCfaCfcUfgauucUfguuUfcUfgAfsgsuAu  828 110 1533-AS07 dTsGfsaCfaCfcUfgauucUfgUfuucUfgAfsgsuAu  829 110 1533-AS08 dTsGfsaCfaCfcUfgAfuucUfguuucUfgAfsgsuAu  830 110 1533-AS09 dTsGfsaCfaCfcUfgAfuucUfguuUfcugAfsgsuAu  831 110 1533-AS10 dTsGfsaCfaCfcUfgAfuucUfgUfuucugAfsgsuAu  832 110 1533-AS11 dTsGfsaCfaCfcUfgAfuucUfguuucugAfsgsuAu  833 110 1533-AS12 dTsGfsaCfaCfcUfgAfuucUfguuucUfgasgsuAu  834 110 1533-AS13 dTsGfsaCfaCfcUfgAfuucUfguuUfcugasgsuAu  835 110 1533-AS16 dTsgsaCfaCfcugAfuucUfgUfuUfcUfgAfsgsuAu  836 110 1533-AS17 dTsgsaCfaCfcUfgauucUfgUfuUfcUfgAfsgsuAu  837 110 1533-AS19 usgsaCfaCfcugauucUfgUfuUfcUfgAfsgsuAu  838 154 1533-AS20 usGfsaCfaCfcugAfuucUfguuUfcUfgAfsgsuAu  839 154 1533-AS21 usGfsaCfaCfcUfgauucUfguuUfcUfgAfsgsuAu  840 154 1533-AS22 usGfsaCfaCfcUfgauucUfgUfuucUfgAfsgsuAu  841 154 1533-AS23 usGfsaCfaCfcUfgAfuucUfguuucUfgAfsgsuAu  842 154 1533-AS24 usGfsaCfaCfcUfgAfuucUfguuUfcugAfsgsuAu  843 154 1533-AS25 usGfsaCfaCfcUfgAfuucUfgUfuucugAfsgsuAu  844 154 1533-AS26 usGfsaCfaCfcUfgAfuucUfguuucugAfsgsuAu  845 154 1533-AS27 usGfsaCfaCfcUfgAfuucUfguuucUfgasgsuAu  846 154 1533-AS28 usGfsaCfaCfcUfgAfuucUfguuUfcugasgsuAu  847 154 1533-CfinAS dTsGfsacaccUfgAfuucUfgUfuUfcUfgAfsgsuAu  848 110 AM05490-AS usGfsasGfaAfuGfaGfcCfuCfgAfuAfausu 1262 177 AM05492-AS cPrpTMsCfsgsUfaUfaAfCfAfaUfaAfgGfgGfcusu 1263 178 AM05493-AS cPrpTMsCfsgsUfaUfaAfcAfaUfaAfgGfgGfcusu 1264 178 AM05495-AS usCfsguauaaCfaaUfaAfgggGfcugCfscsuAu 1265 156 AM05496-AS usCfsguaUfaaCfaaUfaAfgggGfcugCfscsuAu 1266 156 AM05497-AS usCfsgUfaUfaacaaUfaAfgGfgGfcsUfsu 1267 164 AM05498-AS usCfsgsUfaUfaAfCfAfaUfaAfgGfgGfcusu 1268 164

TABLE 2A LPA RNAi agent sense strands havingmodified nucleotides. Sense SEQ SEQ Strand ID SS Sequence 5′-3′ ID NO. ID NO. AM01173-SS AfcGfcAfgAfaGfgGfaCfuGfcCfgAf(invdT)  849  190 AM01174-SS GfgGfgUfgCfaGfgAfgUfgCfuAfcAf(invdT)  850  191 AM01175-SS CfuGfuGfgCfaGfcCfcCfuUfaUfuAf(invdT)  851  192 AM01176-SS GfgCfaGfcCfcCfuUfaUfuGfuUfaAf(invdT)  852  193 AM01177-SS AfgCfcCfcUfuAfuUfgUfuAfuAfcAf(invdT)  853  194 AM01178-SS GfcCfcCfuUfaUfuGfuUfaUfaCfgAf(invdT)  854  195 AM01179-SS UfgAfcAfcAfaUfgCfuCfaGfaCfgAf(invdT)  855  196 AM01180-SS GfaCfaCfaAfuGfcUfcAfgAfcGfcAf(invdT)  856  197 AM01181-SS AfcAfcAfaUfgCfuCfaGfaCfgCfaAf(invdT)  857  198 AM01182-SS AfcAfaUfgCfuCfaGfaCggCfaGfaAf(invdT)  858  199 AM01183-SS CfuGfcCfgAfaAfuCfvAfgAfuCfcAf(invdT)  859  200 AM01184-SS GfcCfgAfaAfuCfcAfgAfuCfcUfgAf(invdT)  860  201 AM01185-SS UfgAfcAfcGfaUfgCfuCfaGfaUfgAf(invdT)  861  202 AM01186-SS GfaCfaCfgAfuGfcUfcAfgAfuGfcAf(invdT)  862  203 AM01187-SS AfcAfcGfaUfgCfuCfaGfaUfgCfaAf(invdT)  863  204 AM01188-SS AfcGfaUfgCfuCfaGfaUfgCfaGfaAf(invdT)  864  205 AM01189-SS UfcCfaAfgCfcUfaGfaGfgCfuUfuAf(invdT)  865  206 AM01190-SS AfgGfaAfaCfcCfvCfgGfgGfuAfcAf(invdT)  866  207 AM01191-SS GfgAfaAfcCfcCfcGfgGfgUfaCfaAf(invdT)  867  208 AM01192-SS GfaAfaCfcCfcCfgGfgGfuAfcAfgAf(invdT)  868  209 AM01193-SS UfgCfuAfcUfaCfcAfuUfaUfgGfaAf(invdT)  869  210 AM01194-SS GfcUfaCfuAfcCfaUfuAfuGfgAfcAf(invdT)  870  211 AM01195-SS CfuAfcCfaUfuAfuGfgAfcAfgAfgAf(invdT)  871  212 AM01196-SS AfcCfaCfaCfcAfgCfaUfaGfuCfgAf(invdT)  872  213 AM01197-SS CfcAfcAfcCfaGfcAfuAfgUfcGfgAf(invdT)  873  214 AM01198-SS CfaCfaCfcAfgCdaUfaGfuCfgGfaAf(invdT)  874  215 AM01199-SS CfaCfcAfgCfaUfaGfuCfgGfaCfcAf(invdT)  875  216 AM01200-SS AfuAfgUfcGfgAfcCfvCfaGfaAfaAf(invdT)  876  217 AM01201-SS UfaGfuCfgGfaCfcCfcAfgAfaAfaAf(invdT)  877  218 AM01202-SS CfcAfgAfuGfcUfgAfgAfuUfcGfcAf(invdT)  878  219 AM01203-SS GfcUfgAfgAfuUfcGfcCfcUfuGfgAf(invdT)  879  220 AM01204-SS CfuGfaGfaUfuCfgCfcCfuUfgGfuAf(invdT)  880  221 AM01205-SS UfgAfgAfuUfcGfcCfcUfuGfgUfgAf(invdT)  881  222 AM01206-SS GfaGfaUfuCfgCfvCfuUfgGfuGfuAf(invdT)  882  223 AM01207-SS AfuGfgAfuCfvCfaGfuGfuCfaGfgAf(invdT)  883  224 AM01208-SS GfaAfuCfaAfgUfgUfcCfuUfgCfaAf(invdT)  884  225 AM01209-SS AfaUfcAfaGfuGfuCfcUfuGfcAfaAf(invdT)  885  226 AM01210-SS GfaAfgCfaCfcAfaCfgGfaGfcAfaAf(invdT)  886  227 AM01211-SS GfaGfuUfaUfcGfaGfgCfuCfaUfuAf(invdT)  887  228 AM01212-SS AfgUfuAfuCfgAfgGfcUfcAfuUfcAf(invdT)  888  229 AM01213-SS GfaCfaAfcAfgAfaUfaUfuAfuCfcAf(invdT)  889  230 AM01214-SS CfuUfgGfuGfuUfaUfaCfcAfuGfgAf(invdT)  890  231 AM01215-SS GfgUfgUfuAfuAfcCfaUfgGfaUfcAf(invdT)  891  232 AM01216-SS UfaUfaCfcAfuGfgAfuCfvCfaAfuAf(invdT)  892  233 AM01217-SS AfuAfcCfaUfgGfaUfcCfcAfaUfgAf(invdT)  893  234 AM01218-SS UfaCfcAfuGfgAfuCfcCfaAfuGfuAf(invdT)  894  235 AM01219-SS AfcCfaUfgGfaUfcCfcAfaUfgUfcAf(invdT)  895  236 AM01220-SS GfcAfaCfcUfgAfcAfcAfaUfgUfcAf(invdT)  896  237 AM01221-SS CfuGfaCfaCfaAfuGfuCfcAfgUfgAf(invdT)  897  238 AM01222-SS CfcAfgUfgAfcAfgAfaUfcAfaGfuAf(invdT)  898  239 AM01223-SS UfuAfuCfgAfgGfcUfcAfuUfcUfcAf(invdT)  899  240 AM01224-SS AfgAfaUfaCfuAfcCfcAfaAfuGfgAf(invdT)  900  241 AM01225-SS AfaUfaCfuAfcCfcAfaAfuGfgUfgAf(invdT)  901  242 AM01226-SS AfuAfcUfaCfcCfaAfaUfgGfuGfgAf(invdT)  902  243 AM01227-SS AfuUfcGfcCfcUfuGfgUfgUfuAfuAf(invdT)  903  244 AM01228-SS UfaUfaCfcAfuGfgAfuCfcCfaGfuAf(invdT)  904  245 AM01229-SS AfuAfcCfaUfgGfaUfcCfcAfgUfgAf(invdT)  905  246 AM01230-SS CfaCfaAfcUfcCfcAfcGfgUfgGfuAf(invdT)  906  247 AM01231-SS AfaGfaAfcAfuGfuCfaGfuCfuUfgAf(invdT)  907  248 AM01232-SS AfgUfgUfcCfuCfaCfaAfcUfcCfcAf(invdT)  908  249 AM01233-SS AfaCfaAfgCfaCfcAfcCfuGfaGfaAf(invdT)  909  250 AM01234-SS CfcUfgAfgAfaAfaGfcCfcUfgUfgAf(invdT)  910  251 AM01235-SS UfgAfuAfcCfaCfaCfuGfgCfaUfcAf(invdT)  911  252 AM01236-SS GfaUfaCfcAfcAfcUfgGfcAfuCfaAf(invdT)  912  253 AM01237-SS GfaAfaCfaGfaAfuCfaGfgUfgUfcAf(invdT)  913  254 AM01238-SS AfaAfcAfgAfaUfcAfgGfuGfuCfcAf(invdT)  914  255 AM01239-SS CfaGfaAfuCfaGfgUfgUfcCfuAfgAf(invdT)  915  256 AM01795-SS CfcUfgUfgGfcAfgCfcCfcUfuAfuAf(invdT)  916  257 AM01797-SS UfgGfcAfgCfcCfcUfuAfuUfgUfuAf(invdT)  917  258 AM01799-SS AfcAfcCfaGfcAfuAfgUfcGfgAfcAf(invdT)  918  259 AM01801-SS GfgAfaUfcCfaGfaUfgCfuGfaGfaAf(invdT)  919  260 AM01803-SS UfcCfaGfaUfgCfuGfaGfaUfuCfgAf(invdT)  920  261 AM01805-SS AfuGfcUfgAfgAfuUfcGfcCfcUfuAf(invdT)  921  262 AM01807-SS CfcAfuGfgAfuCfcCfaGfuGfuCfaAf(invdT)  922  263 AM01809-SS CfuGfaAfgAfaGfcAfcCfaAfcGfgAf(invdT)  923  264 AM01811-SS UfcCfaGfuGfaCfaGfaAfuCfaAfgAf(invdT)  924  265 AM01813-SS CfuCfaCfaAfcUfcCfcAfcGfgUfgAf(invdT)  925  266 AM01815-SS AfgAfaUfcAfgGfuGfuCfcUfaGfaAf(invdT)  926  267 AM01817-SS UfcAfgGfuGfuCfcUfaGfaGfaCfuAf(invdT)  927  268 AM02006-SS (Chol-TEG)uAuAfgCfcCfcUfUfAfuUfgUfuAfuAfcAf(invdT)  928  269 AM02010-SS (Chol-TEG)uAuGfcCfcCfuUfAfUfuGfuUfaUfaCfgAf(invdT)  929  270 AM02014-SS (Chol-TEG)uAuGfaCfaCfaAfUfGfcUfcAfgAfcGfcAf(invdT)  930  271 AM02018-SS (Chol-TEG)uAuAfcAfcAfaUfGfCfuCfaGfaCfgCfaAf(invdT)  931  272 AM02022-SS (Chol-TEG)uAuUfuAfuCfgAfGfGfcUfcAfuUfcUfcAf(invdT)  932  273 AM02026-SS (Chol-TEG)uAuGfaAfaCfaGfAfAfuCfaGfgUfgUfcAf(invdT)  933  274 AM02030-SS (Chol-TEG)uAuAfcAfcCfaGfCfAfuAfgUfcGfgAfcAf(invdT)  934  275 AM02034-SS (Chol-TEG)uAuUfcCfaGfaUfGfCfuGfaGfaUfuCfgAf(invdT)  935  276 AM02038-SS (Chol-TEG)uAuAfuGfcUfgAfgAfuUfcGfcCfcUfuAf(invdT)  936  277 AM02042-SS (Chol-TEG)uAuCfcAfuGfgAfUfCfcCfaGfuGfuCfaAf(invdT)  937  278 AM02211-SS UfgUfgGfcAfGfCfcCfcUfuAfuUfgAf(invdT)  938  279 AM02212-SS CfaCfaAfuGfCfUfcAfgAfcGfcAfgAf(invdT)  939  280 AM02213-SS CfcGfaAfaUfCfCfaGfaUfcCfuGfuAf(invdT)  940  281 AM02214-SS GfaCfuGfaGfGfAfaAfcCfcCfcGfgAf(invdT)  941  282 AM02215-SS CfuAfcUfaCfCfAfuUfaUfgGfaCfaAf(invdT)  942  283 AM02216-SS AfcUfaCfcAfUfUfaUfgGfaCfaGfaAf(invdT)  943  284 AM02217-SS UfaCfcAfuUfAfUfgGfaCfaGfaGfuAf(invdT)  944  285 AM02218-SS AfcCfaUfuAfUfGfgAfcAfgAfgUfuAf(invdT)  945  286 AM02219-SS AfgAfuGfcUfGfAfgAfuUfcGfcCfcAf(invdT)  946  287 AM02220-SS GfaUfgCfuGfAfGfaUfuCfgCfcCfuAf(invdT)  947  288 AM02221-SS AfgAfuUfcGfCfCfcUfuGfgUfgUfuAf(invdT)  948  289 AM02222-SS GfaCfaGfaAfUfCfaAfgUfgUfcCfuAf(invdT)  949  290 AM02223-SS AfcAfuGfuCfAfGfuCfuUfgGfuCfcAf(invdT)  950  291 AM02224-SS CfcAfaAfuGfGfUfgGfcCfuGfaCfcAf(invdT)  951  292 AM02225-SS UfgGfuGfuUfAfUfaCfcAfuGfgAfuAf(invdT)  952  293 AM02226-SS UfgUfuAfuAfCfCfaUfgGfaUfcCfcAf(invdT)  953  294 AM02227-SS AfaCfcUfgAfCfAfcAfaUfgUfcCfaAf(invdT)  954  295 AM02228-SS AfaUfgUfcCfAfGfuGfaCfaGfaAfuAf(invdT)  955  296 AM02229-SS UfgUfuUfcUfGfAfaCfaAfgCfaCfcAf(invdT)  956  297 AM02230-SS UfaUfcGfaGfGfCfuCfaUfuCfuCfcAf(invdT)  957  298 AM02231-SS UfcGfaGfgCfUfCfaUfuCfuCfcAfcAf(invdT)  958  299 AM02232-SS UfcCfuCfaCfAfAfcUfcCfcAfcGfgAf(invdT)  959  300 AM02233-SS CfaAfcUfcCfCfAfcGfgUfgGfuCfcAf(invdT)  960  301 AM02234-SS GfcUfcCfuUfCfUfgAfaCfaAfgCfaAf(invdT)  961  302 AM02235-SS AfuAfcCfaCfAfCfuGfgCfaUfcAfgAf(invdT)  962  303 AM02236-SS AfcAfgAfaUfCfAfgGfuGfuCfcUfaAf(invdT)  963  304 AM02237-SS GfaAfuCfaGfGfUfgUfcCfuAfgAfgAf(invdT)  964  305 AM02238-SS AfaUfcAfgGfUfGfuCfcUfaGfaGfaAf(invdT)  965  306 AM02239-SS AfuCfaGfgUfGfUfcCfuAfgAfgAfcAf(invdT)  966  307 AM02441-SS uAuAusAfsgUfuAfuCfgAfgGfcUfcAfuUfcUfcAf(C6-SS-Alk-Me)  967  308 AM02442-SS uAuAusAfsgUfuAfuCfgaGfGfcUfcAfuUfcUfcAf(C6-SS-Alk-Me)  968  308 AM02443-SS uAuAusAfsgUfuAfuCfGfaGfGfcUfcAfuUfcUfcAf(C6-SS-Alk-Me)  969  308 AM02444-SS uAuAusasGfuUfaUfcGfaGfGfcUfcAfuUfcUfcAf(C6-SS-Alk-Me)  970  308 AM02445-SS uAuAusCfsaGfaAfaCfaGfaAfuCfaGfgUfgUfcAf(C6-SS-Alk-Me)  971  309 AM02446-SS uAuAusCfsaGfaAfaCfagAfAfuCfaGfgUfgUfcAf(C6-SS-Alk-Me)  972  309 AM02447-SS uAuAusCfsaGfaAfaCfAfgAfAfuCfaGfgUfgUfcAf(C6-SS-Alk-Me)  973  309 AM02448-SS uAuAuscsAfgAfaAfcAfgAfAfuCfaGfgUfgUfcAf(C6-SS-Alk-Me)  974  309 AM02537-SS uAuAusCfsaGfcCfcCfuUfAfUfuGfuUfaUfaCfgAf(C11-PEG3-NAG3)  975  310 AM02538-SS uAuAusCfsuGfaCfaCfaAfUfGfcUfcAfgAfcGfcAf(C11-PEG3-NAG3)  976  311 AM02539-SS uAuAusUfsgAfcAfcAfaUfGfCfuCfaGfaCfgCfaAf(C11-PEG3-NAG3)  977  312 AM02540-SS uAuAusAfsgUfuAfuCfgAfGfGfcUfcAfuUfcUfcAf(C11-PEG3-NAG3)  978  308 AM02541-SS uAuAusCfsaGfaAfaCfaGfAfAfuCfaGfgUfgUfcAf(C11-PEG3-NAG3)  979  309 AM02542-SS uAuAusAfsgAfuGfcUfgAfGfAfuUfcGfcCfcUfuAf(C11-PEG3-NAG3)  980  313 AM02793-SS gsCfsaGfcCfcCfuUfaUfuGfuUfa(invdA)  981  314 AM02794-SS gsCfscCfcUfuAfuUfgUfuAfuAfc(invdA)  982  315 AM02795-SS csCfscCfuUfaUfuGfuUfaUfaCfg(invdA)  983  316 AM02796-SS asCfsaCfaAfuGfcUfcAfgAfcGfc(invdA)  984  317 AM02797-SS csAfscAfaUfgCfuCfaGfaCfgCfa(invdA)  985  318 AM02798-SS csCfsgAfaAfuCfcAfgAfuCfcUfg(invdA)  986  319 AM02799-SS csAfscGfaUfgCfuCfaGfaUfgCfa(invdA)  987  320 AM02800-SS csCfsaCfaCfcAfgCfaUfaGfuCfg(invdA)  988  321 AM02801-SS usAfsgUfcGfgAfcCfcCfaGfaAfa(invdA)  989  322 AM02802-SS csAfsgAfuGfcUfgAfgAfuUfcGfc(invdA)  990  323 AM02803-SS asAfsuCfaAfgUfgUfcCfuUfgCfa(invdA)  991  324 AM02804-SS asGfsuUfaUfcGfaGfgCfuCfaUfu(invdA)  992  325 AM02805-SS gsUfsuAfuCfgAfgGfcUfcAfuUfc(invdA)  993  326 AM02806-SS csAfsaCfcUfgAfcAfcAfaUfgUfc(invdA)  994  327 AM02807-SS usAfsuCfgAfgGfcUfcAfuUfcUfc(invdA)  995  328 AM02808-SS gsAfsaUfaCfuAfcCfcAfaAfuGfg(invdA)  996  329 AM02809-SS asUfsaCfuAfcCfcAfaAfuGfgUfg(invdA)  997  330 AM02810-SS asAfsaCfaGfaAfuCfaGfgUfgUfc(invdA)  998  331 AM02811-SS asAfscAfgAfaUfcAfgGfuGfuCfc(invdA)  999  332 AM02812-SS CfsasGfcCfcCfuUfaUfuGfuUfa(invdA) 1000  333 AM02813-SS CfscsCfcUfuAfuUfgUfuAfuAfc(invdA) 1001  334 AM02814-SS CfscsCfuUfaUfuGfuUfaUfaCfg(invdA) 1002  335 AM02815-SS CfsasCfaAfuGfcUfcAfgAfcGfc(invdA) 1003  336 AM02816-SS AfscsAfaUfgCfuCfaGfaCfgCfa(invdA) 1004  337 AM02817-SS CfsgsAfaAfuCfcAfgAfuCfcUfg(invdA) 1005  338 AM02818-SS AfscsGfaUfgCfuCfaGfaUfgCfa(invdA) 1006  339 AM02819-SS CfsasCfaCfcAfgCfaUfaGfuCfg(invdA) 1007  340 AM02820-SS AfsgsUfcGfgAfcCfcCfaGfaAfa(invdA) 1008  341 AM02821-SS AfsgsAfuGfcUfgAfgAfuUfcGfc(invdA) 1009  342 AM02822-SS AfsusCfaAfgUfgUfcCfuUfgCfa(invdA) 1010  343 AM02823-SS GfsusUfaUfcGfaGfgCfuCfaUfu(invdA) 1011  344 AM02824-SS UfsusAfuCfgAfgGfcUfcAfuUfc(invdA) 1012  345 AM02825-SS AfsasCfcUfgAfcAfcAfaUfgUfc(invdA) 1013  346 AM02826-SS AfsusCfgAfgGfcUfcAfuUfcUfc(invdA) 1014  347 AM02827-SS AfsasUfaCfuAfcCfcAfaAfuGfg(invdA) 1015  348 AM02828-SS UfsasCfuAfcCfcAfaAfuGfgUfg(invdA) 1016  349 AM02829-SS AfsasCfaGfaAfuCfaGfgUfgUfc(invdA) 1017  350 AM02830-SS AfscsAfgAfaUfcAfgGfuGfuCfc(invdA) 1018  351 AM02861-SS uAuAusAfsgUfuauCfgAfGfGfcUfcAfuUfcUfcAf(C11-PEG3-NAG3) 1019  308 AM02941-SS uAuAusasguuaucgAfgGfcucauucuca(C11-PEG3-NAG3) 1020  308 AM02942-SS uAuAusasguuaucgaGfGfcucauucuca(C11-PEG3-NAG3) 1021  308 AM02946-SS uAuAuscsagaaaCfagAfAfuCfagguguca(C11-PEG3-NAG3) 1022  309 AM02947-SS uAuAuscsagaaaCfaGfaAfuCfagguguca(C11-PEG3-NAG3) 1023  309 AM02948-SS uAuAuscsagaaacaGfaAfucagguguca(C11-PEG3-NAG3) 1024  309 AM02949-SS uAuAuscsagaaacagAfAfucagguguca(C11-PEG3-NAG3) 1025  309 AM03030-SS (Stearyl)uAuAusCfsaGfaAfaCfaGfAfAfuCfaGfgUfgUfcAf(C11-PEG3-NAG3) 1026  309 AM03036-SS uAuAusCfsagaAfaCfaGfAfAfuCfaGfgUfgUfcAf(C11-PEG3-NAG3) 1027  309 AM03037-SS uAuAusCfsagaaaCfaGfAfAfuCfaGfgUfgUfcAf(C11-PEG3-NAG3) 1028  309 AM03038-SS uAuAusCfsagaaaCfagaAfuCfaggUfgUfcAf(C11-PEG3-NAG3) 1029  309 AM03039-SS uAuAusCfsaGfaAfaCfaGfAfAfuCfagGfuGfucAf(C11-PEG3-NAG3) 1030  309 AM03042-SS uAuAusCfsaGfaAfaCfaGfAfAfucagguguca(C11-PEG3-NAG3) 1031  309 AM03060-SS uAuAusCfsaGfaAfaCfaGfAfAfuCfaggugUfca(C11-PEG3-NAG3) 1032  309 AM03061-SS uAuAusCfsaGfaAfaCfaGfAfAfuCfagguguca(C11-PEG3-NAG3) 1033  309 AM03062-SS uAuAusCfsagaaaCfaGfAfAfuCfaggugUfca(C11-PEG3-NAG3) 1034  309 AM03064-SS uAuAusCfsaGfaAfaCfaGfaAfuCfaGfgugucAf(C11-PEG3-NAG3) 1035  309 AM03122-SS uAuAusAfsgUfuAfuCfgAfGfGfcUfcAfuUfcUfCMAM(C11-PEG3-NAG3) 1036  308 AM03123-SS uAuAUuNAAfsgsUfuAfuCfgAfGfGfcUfcAfuUfcUfcAf(C11-PEG3-NAG3) 1037  308 AM03124-SS uAuAuAfsgsUfuAfuCfgAfGfGfcUfcAfuUfcUfcAf(C11-PEG3-NAG3) 1038  308 AM03125-SS uAuAusCfsaGfcCfcCfuUfAfUfuGfuUfaUfaCfga(C11-PEG3-NAG3) 1039  310 AM03126-SS uAuAuscsaGfcCfcCfuUfAfUfuGfuUfaUfaCfgAf(C11-PEG3-NAG3) 1040  310 AM03128-SS uAuAuscsaGfcCfcCfuUfAfUfuGfuUfaUfaCfga(C11-PEG3-NAG3) 1041  310 AM03144-SS uAuAusAfsgUfuAfuCfgAfGfGfcUfcAfuUfcUfcAf(C6-PEG4-NAG3) 1042  308 AM03220-SS uAuAusAfsgUfuAfuCfgAfGfGfcUfcauucuca 1043  308 1532-SS01 AM03221-SS uAuAusAfsgUfuAfuCfgAfGfGfcucauucuca 1044  308 AM03222-SS uAuAusAfsguuauCfgAfGfGfcUfcauucuca 1045  308 AM03223-SS uAuAusAfsguuauCfgAfGfGfcucauucuca 1046  308 AM03224-SS uAuAusasguuauCfgAfGfGfcucauucuca 1047  308 AM03225-SS uAuAusasguuaucgAfGfGfcucauucuca 1048  308 AM03226-SS uAuAusAfsgUfuAfuCfgAfGfdGcUfcauucuca 1049  308 AM03227-SS uAuAusAfsgUfuAfuCfgAfGfdGcucauucuca 1050  308 AM03228-SS uAuAusAfsguuauCfgAfGfdGcUfcauucuca 1051  308 AM03229-SS uAuAusAfsguuauCfgAfGfdGcucauucuca 1052  308 AM03230-SS uAuAusasguuauCfgAfGfdGcucauucuca 1053  308 AM03231-SS uAuAusasguuaucgAfGfdGcucauucuca 1054  308 AM03232-SS uAuAusAfsgUfuAfuCfgaGfGfcUfcauucuca 1055  308 AM03233-SS uAuAusAfsgUfuAfuCfgaGfGfcucauucuca 1056  308 AM03234-SS uAuAusAfsguuauCfgaGfGfcUfcauucuca 1057  308 AM03235-SS uAuAusAfsguuauCfgaGfGfcucauucuca 1058  308 AM03236-SS uAuAusasguuauCfgaGfGfcucauucuca 1059  308 AM03237-SS uAuAusasguuaucgaGfGfcucauucuca 1060  308 AM03238-SS uAuAusAfsgUfuAfuCfgAfGfGfcUfcauucuca(C11-PEG3-NAG3) 1061  308 AM03240-SS uAuAusAfsguuauCfgAfGfGfcUfcauucuca(C11-PEG3-NAG3) 1062  308 AM03330-SS uAuAusAfsgUfuAfuCfgAfGfGfcUfcAfuUfcUfcAf 1063  308 1532-SS00 AM03291-SS uAuAusCfsaGfcCfcCfuUfAf UfuGfuUfaUfaCfgAf 1064  310 AM03292-SS uAuAusCfsagcCfcCfuUfaUfuguUfaUfaCfga 1065  310 AM03293-SS uAuAusCfsagcCfcCfuUfaUfuguuauaCfga 1066  310 AM03294-SS uAuAuscsagccccuUfaUfuguuauacga 1067  310 AM03295-SS uAuAuscsagccccuuAfUfuguuauacga 1068  310 AM03296-SS uAuAusCfsagcCfcCfuUfAfUfuguUfaUfaCfga 1069  310 AM03297-SS uAuAusCfsagcCfcCfuUfAfUfuguuauaCfga 1070  310 AM03298-SS uAuAuscsagccccuUfAfUfuguuauacga 1071  310 AM03299-SS uAuAusCfsagcCfcCfuuAfUfuguuauaCfga 1072  310 AM03277-SS uAuAuscsagccccuUfaUfuguuauacga(C11-PEG3-NAG3) 1073  310 AM03275-SS uAuAusCfsagcCfcCfuUfaUfuguUfaUfaCfga(C11-PEG3-NAG3) 1074  310 AM03276-SS uAuAusCfsagcCfcCfuUfaUfuguuauaCfga(C11-PEG3-NAG3) 1075  310 AM03278-SS uAuAuscsagccccuuAfUfuguuauacga(C11-PEG3-NAG3) 1076  310 AM03287-SS uAuAusCfsagcCfcCfuUfAfUfuguUfaUfaCfga(C11-PEG3-NAG3) 1077  310 AM03288-SS uAuAusCfsagcCfcCfuUfAfUfuguuauaCfga(C11-PEG3-NAG3) 1078  310 AM03289-SS uAuAuscsagccccuUfAfUfuguuauacga(C11-PEG3-NAG3) 1079  310 AM03290-SS uAuAusCfsagcCfcCfuuAfUfuguuauaCfga(C11-PEG3-NAG3) 1080  310 AM03243-SS uAuAusasguuaucgAfGfGfcucauucuca(C11-PEG3-NAG3) 1081  308 AM03424-SS (Chol-TEG)uAuAusasguuaucgaGfGfcucauucuc(invdA) 1082  308 AM03425-SS (Chol-TEG)uAuAusasguuaucgaGfGfcucauucuca 1083  308 AM03426-SS (Chol-TEG)uAuAusAfgUfuAfuCfgAfGfGfcUfcAfuUfcUfc(invdA) 1084  308 AM03457-SS CfscsCfcUfuAfuUfgUfuAfuAfca(NAG13) 1085  334 AM03458-SS CfscsCfuUfaUfuGfuUfaUfaCfga(NAG13) 1086  335 AM03459-SS AfsgsAfuGfcUfgAfgAfuUfcGfca(NAG13) 1087  342 AM03460-SS GfsusUfaUfcGfaGfgCfuCfaUfua(NAG13) 1088  344 AM03461-SS AfsusCfgAfgGfcUfcAfuUfcUfca(NAG13) 1089  347 AM03462-SS AfsasCfaGfaAfuCfaGfgUfgUfca(NAG13) 1090  350 AM03489-SS uAuAusasguuaucgaGfGfcucauucuca(NAG13) 1091  308 AM03492-SS uAuAusCfsaGfcCfcCfuUfAfUfuGfuUfaUfaCfga(NAG13) 1092  310 AM03544-SS uAuAuscsagcccCfuUfaUfuguuauacga(NAG13) 1093  310 AM03545-SS uAuAuscsagccccuuAfUfuGfuuauacga(NAG13) 1094  310 AM03546-SS uAuAuscsagccccuUfAfUfuguuauacga(NAG13) 1095  310 AM03547-SS uAuAusAfsgUfuAfuCfgAfGfGfcUfcAfuUfcUfcAf(NAG13) 1096  308 AM03650-SS uAuAusasguuaucgAfGfGfcucauucuca(NAG13) 1097  308 AM03651-SS uAuAuscsaGfcCfcCfuUfAfUfuGfuUfaUfaCfga(NAG13) 1098  310 AM03670-SS uAuAuscsagcgccuUfAfUfuguuauacga(NAG13) 1099  352 AM03683-SS uAuAuscsaGfcCfcCfuUfAfUfuGfuUfaUfaCfga 1100  310 AM03741-SS cscsccUfUfAfuuguuauaca(NAG13) 1101  334 AM03742-SS cscsccUfUfAfuuguuauaCMAM(NAG13) 1102  334 AM03743-SS CMsCMsccUfUfAfuuguuauaCMAM(NAG13) 1103  334 AM03746-SS cscscuUfAfUfuguuauacga(NAG13) 1104  335 AM03747-SS cscscuUfAfUfuguuauacGMAM(NAG13) 1105  335 AM03748-SS CMsCMscuUfAfUfuguuauacGMAM(NAG13) 1106  335 AM03751-SS asuscgAfGfGfcucauucuca(NAG13) 1107  347 AM03752-SS asuscgAfGfGfcucauucuCMAM(NAG13) 1108  347 AM03753-SS AMsTMscgAfGfGfcucauucuCMAM(NAG13) 1109  353 AM03757-SS asascaGfAfAfucagguguca(NAG13) 1110  350 AM03758-SS asascaGfAfAfucagguguCMAM(NAG13) 1111  350 AM03759-SS AMsAMscaGfAfAfucagguguCMAM(NAG13) 1112  350 AM03859-SS (NAG18)uauausasguuaucgAfGfGfcucauucuc(invdA) 1113  308 AM03861-SS (NAG18)uauauscsaGfcCfcCfuUfAfUfuGfuUfaUfaCfg(invdA) 1114  310 AM03879-SS (NAG4)uscaGfcCfcCfuUfAfUfuGfuUfaUfaCfgausu(invAb) 1115  354 AM03880-SS (NAG4)uscaGfcCfcCfuUfAfUfuGfuUfaUfaCfgsa(invAb) 1116  355 AM03881-SS (NAG24)uscaGfcCfcCfuUfAfUfuGfuUfaUfaCfgausu(invAb) 1117  354 AM03882-SS (NAG4)usaguuaucgAfGfGfcucauucucausu(invAb) 1118  356 AM03928-SS uAuAuscsagcccCfuUfAfUfuguuauacga(NAG13) 1119  310 AM03931-SS uAuAusasguuauCfgAfGfGfcucauucuca(NAG13) 1120  308 AM03968-SS (NAG4)uauauscaGfcCfcCfuUfAfUfuGfuUfaUfaCfgs(invdA) 1121  310 AM03970-SS (NAG4)(invAb)GfcCfcCfuUfAfUfuGfuUfaUfaCfgausu(invAb) 1122  357 AM04138-SS (NAG25)uauausasguuaucgAfGfGfcucauucuc(invdA) 1123  308 AM04152-SS (Alk-PEG5-C6)uauausasguuaucgAfGfGfcucauucuCM(invdA) 1124  308 AM04214-SS (Alk-SMPT-C6)uauausasguuaucgAfGfGfcucauucuCM(invdA) 1125  308 AM04233-SS (NAG26)uauausasguuaucgAfGfGfcucauucuCM(invdA) 1126  308 AM04372-SS (NAG27)uauausasguuaucgAfGfGfcucauucuCM(invdA) 1127  308 AM04381-SS (NAG25)auauscsagccccuUfAfUfuguuauacga(invdT) 1128  358 AM04382-SS (NAG25)uauscsagccccuUfAfUfuguuauacgau(invdT) 1129  359 AM04391-SS (NAG25)auausasguuaucgAfGfGfcucauucuca(invdT) 1130  360 AM04392-SS (NAG25)uausasguuaucgAfGfGfcucauucucau(invdT) 1131  361 AM04412-SS (NAG25)uauauscsagccccuUfAfUfuguuauacg(invdA) 1132  310 AM04414-SS (NAG25)(invAb)gccccuUfAfUfuguuauacgauus(invAb) 1133  357 AM04416-SS (NAG25)(invAb)uuaucgAfGfGfcucauucucausu(invAb) 1134  362 AM04496-SS (NAG25)(invAb)GfcCfcCfuUfAfUfuGfuUfaUfaCfgausu(invAb) 1135  357 AM04497-SS (NAG29)uauausasguuaucgAfGfGfcucauucuc(invdA) 1136  308 AM04499-SS (NAG28)(invAb)GfcCfcCfuUfAfUfuGfuUfaUfaCfgausu(invAb) 1137  357 AM04498-SS (NAG29)uauauaasuuaucgaGfGfcucauucucsa(invAb) 1138  363 AM04500-SS (NAG30)(invAb)GfcCfcCfuUfAfUfuGfuUfaUfaCfgausu(invAb) 1139  357 AM04502-SS (NAG25)uauauaasuuaucgaGfGfcucauucucsa(invAb) 1140  363 AM04535-SS (NAG25)uauaucsasgccccuUfAfUfuguuauacg(invdA) 1141  310 AM04536-SS (NAG25)uauaucasgccccuUfAfUfuguuauacg(invdA) 1142  310 AM04537-SS (NAG25)uauauasgsuuaucgAfGfGfcucauucuc(invdA) 1143  308 AM04538-SS (NAG25)uauauagsuuaucgAfGfGfcucauucuc(invdA) 1144  308 AM04543-SS (NAG30)uscaGfcCfcCfuUfAfUfuGfuUfaUfaCfgsa(invAb) 1145  355 AM04578-SS (NAG25)ggcsagccccuUfAfUfuguuauacgAMs(invdT)dT 1146  364 AM04588-SS (NAG25)ggcsagccccuUfAfUfuguuauacgAMsuu(invdT) 1147  365 AM04579-SS (NAG25)GuNAgcsagccccuUfAfUfuguuauacgAMs(invdT)dT 1148  364 AM04580-SS (NAG25)ggcs(invdA)gccccuUfAfUfuguuauacgAMs(invdT)dT 1149  364 AM04581-SS (NAG25)csagccccuUfAfUfuguuauacgAMs(invdT)dTdTdT 1150  366 AM04611-SS (NAG31)(invAb)GfcCfcCfuUfAfUfuGfuUfaUfaCfgausu(invAb) 1151  357 AM04612-SS (NAG32)(invAb)GfcCfcCfuUfAfUfuGfuUfaUfaCfgausu(invAb) 1152  357 AM04669-SS (NAG25)uauauagsusuaucgAfGfGfcucauucuc(invdA) 1153  308 AM04670-SS (NAG25)uauauagususaucgAfGfGfcucauucuc(invdA) 1154  308 AM04671-SS (NAG25)gcgausasguuaucgAfGfGfcucauucuc(invdA) 1155  367 AM04672-SS (NAG25)ugaausasguuaucgAfGfGfcucauucuc(invdA) 1156  368 AM04673-SS (NAG25)aucgusasguuaucgAfGfGfcucauucuc(invdA) 1157  369 AM04674-SS (NAG25)u(invdA)uausasguuaucgAfGfGfcucauucuc(invdA) 1158  308 AM04675-SS (NAG25)uaua(invdA)sasguuaucgAfGfGfcucauucuc(invdA) 1159  370 AM04676-SS (NAG25)uauaus(invdA)sguuaucgAfGfGfcucauucuc(invdA) 1160  308 AM04726-SS (NAG30)aGfcCfcCfuUfAfUfuGfuUfaUfaCfgsa(invAb) 1161  371 AM04727-SS (NAG30)aaGfcCfcCfuUfAfUfuGfuUfaUfaCfgsa(invAb) 1162  372 AM04728-SS (NAG30)sasGfcCfcCfuUfAfUfuGfuUfaUfaCfgas(invAb) 1163  371 AM04729-SS (NAG30)gscaGfcCfcCfuUfAfUfuGfuUfaUfaCfgsa(invAb) 1164  373 AM04737-SS (NAG25)uauauagsuuaucgaGfGfcucauucucsa(invAb) 1165  374 AM04741-SS (NAG30)sgscaGfcCfcCfuUfAfUfuGfuUfaUfaCfgsa(invAb) 1166  373 AM04742-SS (NAG33)(invAb)GfcCfcCfuUfAfUfuGfuUfaUfaCfgausu(invAb) 1167  357 AM04743-SS (NAG34)(invAb)GfcCfcCfuUfAfUfuGfuUfaUfaCfgausu(invAb) 1168  357 AM04744-SS (NAG35)(invAb)GfcCfcCfuUfAfUfuGfuUfaUfaCfgausu(invAb) 1169  357 AM04803-SS (NAG30)acGfcCfcCfuUfAfUfuGfuUfaUfaCfgsa(invAb) 1170  375 AM04804-SS (NAG30)sasaGfcCfcCfuUfAfUfuGfuUfaUfaCfgas(invAb) 1171  372 AM04807-SS (NAG30)sascGfcCfcCfuUfAfUfuGfuUfaUfaCfgas(invAb) 1172  375 AM04806-SS (NAG30)sgscaGfcCfcCfuUfAfUfuGfuUfaUfaCfgas(invAb) 1173  373 AM04808-SS (NAG31)sGfcCfcCfuUfAfUfuGfuUfaUfaCfgausu(invAb) 1174  376 AM04809-SS (NAG31)saGfcCfcCfuUfAfUfuGfuUfaUfaCfgausu(invAb) 1175  377 AM04810-SS (NAG31)sasaGfcCfcCfuUfAfUfuGfuUfaUfaCfgas(invAb) 1176  372 AM04811-SS (NAG31)sasaGfcCfcCfuUfAfUfuGfuUfaUfaCfgausu(invAb) 1177  378 AM04812-SS (NAG31)sasaGfcCfcCfuUfAfUfuGfuUfaUfaCfg(invdA)usu(invAb) 1178  378 AM04813-SS (NAG31)uauausasguuaucgAfGfGfcucauucuc(invdA) 1179  308 AM04816-SS (NAG31)uauscsagccccuUfAfUfuguuauacgs(invdA) 1180  379 AM04817-SS (NAG31)uagscsagccccuUfAfUfuguuauacgs(invdA) 1181  380 AM04835-SS (NAG31)uaucagccccuUfAfUfuguuauacgs(invdA) 1182  379 AM04819-SS (NAG31)sgscagccccuUfAfUfuguuauacgs(invdA) 1183  381 AM04820-SS (NAG31)sgscagccccuUfAfUfuguuauacgsa(invAb) 1184  373 AM04862-SS (NAG25)auaagasguuaucgAfGfGfcucauucuc(invdA) 1185  382 AM04863-SS (NAG25)auaagsasguuaucgAfGfGfcucauucuc(invdA) 1186  382 AM04864-SS (NAG25)auaggcsagccccuUfAfUfuguuauacg(invdA) 1187  383 AM04865-SS (NAG25)auaggscsagccccuUfAfUfuguuauacg(invdA) 1188  383 AM04866-SS (NAG25)scsagccccuUfAfUfuguuauacgs(invdA) 1189  384 AM04867-SS (NAG31)scsagccccuUfAfUfuguuauacgs(invdA) 1190  384 AM04868-SS (NAG25)sgsccccuUfAfUfuguuauacgauus(invAb) 1191  376 AM04869-SS (NAG31)sgsccccuUfAfUfuguuauacgauus(invAb) 1192  376 AM04870-SS (NAG25)sGfsccccuUfAfUfuguuauacgauus(invAb) 1193  376 AM04978-SS (NAG31)sGfscCfcCfuUfAfUfuGfuUfaUfaCfgauus(invAb) 1194  376 AM05070-SS (NAG25)uauauscsagcccc(NOTA-dT)UfAfUfuguuauacg(invdA) 1195  385 AM05072-SS (NAG25)(invAb)GfcCfcCf(NOTA-dT)UfAfUfuGfuUfaUfaCfgausu(invAb) 1196 1241 1532-SS02 uAuAusAfsgUfuAfuCfgAfGfGfcucAfuucuca 1197  308 1532-SS03 uAuAusAfsgUfuAfuCfgAfGfGfcucauUfcuca 1198  308 1532-SS04 uAuAusAfsgUfuAfuCfgAfGfGfcucauucUfca 1199  308 1532-SS05 uAuAusAfsgUfuAfuCfgAfGfGfcucauucucAf 1200  308 1532-SS06 uAuAusAfsgUfuAfuCfgAfgGfcUfcauucucAf 1201  308 1532-SS07 uAuAusAfsgUfuAfuCfgAfgGfcucAfuucucAf 1202  308 1532-SS08 uAuAusAfsgUfuAfuCfgAfgGfcucauUfcucAf 1203  308 1532-SS09 uAuAusAfsgUfuAfuCfgAfgGfcucauucUfcAf 1204  308 1532-SS10 uAuAusAfsgUfuAfuCfgAfgGfcucauucucAf 1205  308 1532-SS11 uAuAusAfsgUfuAfuCfgaGfGfcucauucucAf 1206  308 1532-SS12 uAuAusAfsgUfuAfuCfgagGfcUfcauucucAf 1207  308 1532-SS13 uAuAusAfsgUfuAfuCfgagGfcucAfuucucAf 1208  308 1532-SS14 uAuAusAfsgUfuAfuCfgagGfcucauUfcucAf 1209  308 1532-SS15 uAuAusAfsgUfuAfuCfgagGfcucauucUfcAf 1210  308 1532-SS16 uAuAusAfsgUfuAfuCfgagGfcucauUfcUfcAf 1211  308 1532-SS17 uAuAusAfsgUfuauCfgAfgGfcucauUfcUfcAf 1212  308 1532-SS18 uAuAusAfsgUfuauCfgaGfGfcucauUfcUfcAf 1213  308 1532-SS19 uAuAusAfsgUfuauCfgagGfcUfcauUfcUfcAf 1214  308 1532-SS20 uAuAusAfsgUfuauCfgagGfcucAfuUfcUfcAf 1215  308 1532-SS21 uAuAusAfsgUfuauCfgagGfcUfcAfuUfcUfcAf 1216  308 1532-SS22 uAuAusAfsguuAfuCfgagGfcUfcAfuUfcUfcAf 1217  308 1532-SS23 uAuAusAfsguuauCfgAfgGfcUfcAfuUfcUfcAf 1218  308 1532-SS24 uAuAusAfsguuauCfgaGfGfcUfcAfuUfcUfcAf 1219  308 1533-CfinSS uAuAuscsaGfaAfacaGfAfAfucaGfgUfgUfcAf 1220  309 1533-SS00 uAuAusCfsaGfaAfaCfaGfAfAfuCfaGfgUfgUfcAf 1221  309 1533-SS01 uAuAusCfsaGfaAfaCfaGfAfAfuCfaGfguguca 1222  309 1533-SS02 uAuAusCfsaGfaAfaCfaGfAfAfuCfaggugUfca 1223  309 1533-SS03 uAuAusCfsaGfaAfaCfaGfAfAfuCfaggugucAf 1224  309 1533-SS04 uAuAusCfsaGfaAfaCfaGfAfAfuCfaggUfguca 1225  309 1533-SS05 uAuAusCfsaGfaAfaCfaGfaAfuCfaGfgugucAf 1226  309 1533-SS06 uAuAusCfsaGfaAfaCfaGfaAfuCfaggugUfcAf 1227  309 1533-SS07 uAuAusCfsaGfaAfaCfaGfaAfuCfaggUfgucAf 1228  309 1533-SS08 uAuAusCfsaGfaAfaCfagAfAfuCfaggugUfcAf 1229  309 1533-SS09 uAuAusCfsaGfaAfaCfagaAfuCfaggUfgUfcAf 1230  309 1533-SS10 uAuAusCfsaGfaAfaCfagaAfuCfaGfgugUfcAf 1231  309 1533-SS11 uAuAusCfsaGfaaaCfagAfAfuCfaGfgUfgUfcAf 1232  309 1533-SS20 1533-SS12 uAuAusCfsaGfaaaCfaGfaAfuCfaGfgUfgUfcAf 1233  309 1533-SS13 uAuAusCfsaGfaAfaCfagaAfuCfaGfgUfgUfcAf 1234  309 1533-SS14 uAuAusCfsaGfaaaCfagaAfuCfaGfgUfgUfcAf 1235  309 1533-SS15 uAuAusCfsagaAfaCfagaAfuCfaGfgUfgUfcAf 1236  309 1533-SS16 uAuAusCfsagaaaCfagAfAfuCfaGfgUfgUfcAf 1237  309 1533-SS17 uAuAusCfsagaaaCfaGfaAfuCfaGfgUfgUfcAf 1238  309 1533-SS18 uAuAusCfsagaaaCfaGfAfAfuCfaGfgUfgUfcAf 1239  309 1533-SS19 uAuAusCfsagaAfaCfagAfAfuCfaGfgUfgUfcAf 1240  309 AM05341-SS (NAG37)(invAb)GfcCfcCfuUfAfUfuGfuUfaUfaCfgausu(invAb) 1256  357 AM05342-SS (NAG37)scsagccccuUfAfUfuguuauacgs(invdA) 1257  381 AM05489-SS (NAG25)uauausasguuaucgAfGfGfcucauucucas(invAb) 1269  308 AM05491-SS (NAG25)(invAb)uuaucgAfGfGfcucauucucas(invAb) 1270 1258 AM05494-SS (NAG25)(invAb)GfcCfcCfuUfAfUfuGfuUfaUfaCfgas(invAb) 1271 1259 AM05499-SS (NAG25)(invAb)gccccuUfAfUfuguuauacgausu(invAb) 1272  357 AM05500-SS (NAG25)uauauscsagccccuUfAfUfuguuauacgas(invAb) 1273  310 AM05501-SS (NAG25)(invAb)gccccuUfAfUfuguuauacgas(invAb) 1274 1259 AM05502-SS (NAG25)sasagccccuUfAfUfuguuauacgs(invdA) 1275 1261 AM05503-SS (NAG25)scsagccccuUfAfUfuguuauacgas(invAb) 1276 1260 AM05504-SS (NAG25)sgsccccuUfAfUfuguuauacgas(invAb) 1277  371 AM05505-SS (NAG25)sgsccccuUfAfUfuguuauacgs(invdA) 1278  371 AM05506-SS (NAG25)sasagccccuUfAfUfuguuauacgas(invAb) 1279 1261

A sense strand containing a sequence listed in Table 2B can be hybridized to any antisense strand containing a sequence listed in Table 2A provided the two sequences have a region of at least 90% complementarity over a contiguous 16, 17, 18, 19, 20, or 21 nucleotide sequence. Representative LPA RNAi agents are represented by the Duplex ID Nos. shown in Tables 3A and 3B.

In some embodiments an LPA RNAi agent comprises of any of the Duplex ID Nos. presented herein. In some embodiments an LPA RNAi agent consists of any of the Duplex ID Nos. presented herein. In some embodiments, an LPA RNAi agent comprises the sense strand and antisense strand nucleotide sequences of any of the Duplex ID Nos. presented herein. In some embodiments, an LPA RNAi agent comprises the sense strand and antisense strand nucleotide sequences of any of the Duplex ID Nos. presented herein and a targeting group and/or linking group wherein the targeting group and/or linking group is covalently linked (i.e. conjugated) to the sense strand or the antisense strand. In some embodiments, an LPA RNAi agent comprises the sense strand and antisense strand modified nucleotide sequences of any of the Duplex ID Nos. presented herein. In some embodiments, an LPA RNAi agent comprises the sense strand and antisense strand modified nucleotide sequences of any of the Duplex ID Nos. presented herein and a targeting group and/or linking group wherein the targeting group and/or linking group is covalently linked to the sense strand or the antisense strand.

TABLE 3A LPA RNAi agent duplexes with Duplex ID numbers. Antisense Sense Strand Antisense Sense Strand Antisense Sense Strand Duplex ID Strand ID ID Duplex ID Strand ID ID Duplex ID Strand ID ID AD00571 AM01240-AS AM01173-SS AD02120 AM03257-AS AM03229-SS AD02500 AM03107-AS AM03295-SS AD00572 AM01241-AS AM01174-SS AD02121 AM03257-AS AM03230-SS AD02501 AM03279-AS AM03295-SS AD00573 AM01242-AS AM01175-SS AD02122 AM03257-AS AM03231-SS AD02502 AM03280-AS AM03295-SS AD00574 AM01243-AS AM01176-SS AD02123 AM03257-AS AM03232-SS AD02503 AM03281-AS AM03295-SS AD00575 AM01244-AS AM01177-SS AD02124 AM03257-AS AM03233-SS AD02504 AM03282-AS AM03295-SS AD00576 AM01245-AS AM01178-SS AD02125 AM03257-AS AM03234-SS AD02505 AM03283-AS AM03295-SS AD00577 AM01246-AS AM01179-SS AD02126 AM03257-AS AM03235-SS AD02506 AM03284-AS AM03295-SS AD00578 AM01247-AS AM01180-SS AD02127 AM03257-AS AM03236-SS AD02507 AM03300-AS AM03295-SS AD00579 AM01248-AS AM01181-SS AD02128 AM03257-AS AM03237-SS AD02508 AM03301-AS AM03295-SS AD00580 AM01249-AS AM01182-SS AD02129 AM03258-AS AM03220-SS AD02509 AM03107-AS AM03296-SS AD00581 AM01250-AS AM01183-SS AD02130 AM03258-AS AM03221-SS AD02510 AM03279-AS AM03296-SS AD00582 AM01251-AS AM01184-SS AD02131 AM03258-AS AM03222-SS AD02511 AM03280-AS AM03296-SS AD00583 AM01252-AS AM01185-SS AD02132 AM03258-AS AM03223-SS AD02512 AM03281-AS AM03296-SS AD00584 AM01253-AS AM01186-SS AD02133 AM03258-AS AM03224-SS AD02513 AM03282-AS AM03296-SS AD00585 AM01254-AS AM01187-SS AD02134 AM03258-AS AM03225-SS AD02514 AM03283-AS AM03296-SS AD00586 AM01255-AS AM01188-SS AD02135 AM03258-AS AM03226-SS AD02515 AM03284-AS AM03296-SS AD00587 AM01256-AS AM01189-SS AD02136 AM03258-AS AM03227-SS AD02516 AM03300-AS AM03296-SS AD00588 AM01257-AS AM01190-SS AD02137 AM03258-AS AM03228-SS AD02517 AM03301-AS AM03296-SS AD00589 AM01258-AS AM01191-SS AD02138 AM03258-AS AM03229-SS AD02518 AM03107-AS AM03297-SS AD00590 AM01259-AS AM01192-SS AD02139 AM03258-AS AM03230-SS AD02519 AM03279-AS AM03297-SS AD00591 AM01260-AS AM01193-SS AD02140 AM03258-AS AM03231-SS AD02520 AM03280-AS AM03297-SS AD00592 AM01261-AS AM01194-SS AD02141 AM03258-AS AM03232-SS AD02521 AM03281-AS AM03297-SS AD00593 AM01262-AS AM01195-SS AD02142 AM03258-AS AM03233-SS AD02522 AM03282-AS AM03297-SS AD00594 AM01263-AS AM01196-SS AD02143 AM03258-AS AM03234-SS AD02523 AM03283-AS AM03297-SS AD00595 AM01264-AS AM01197-SS AD02144 AM03258-AS AM03235-SS AD02524 AM03284-AS AM03297-SS AD00596 AM01265-AS AM01198-SS AD02145 AM03258-AS AM03236-SS AD02525 AM03300-AS AM03297-SS AD00597 AM01266-AS AM01199-SS AD02146 AM03258-AS AM03237-SS AD02526 AM03301-AS AM03297-SS AD00598 AM01267-AS AM01200-SS AD02147 AM03259-AS AM03220-SS AD02527 AM03107-AS AM03298-SS AD00599 AM01268-AS AM01201-SS AD02148 AM03259-AS AM03221-SS AD02528 AM03279-AS AM03298-SS AD00600 AM01269-AS AM01202-SS AD02149 AM03259-AS AM03222-SS AD02529 AM03280-AS AM03298-SS AD00601 AM01270-AS AM01203-SS AD02150 AM03259-AS AM03223-SS AD02530 AM03281-AS AM03298-SS AD00602 AM01271-AS AM01204-SS AD02151 AM03259-AS AM03224-SS AD02531 AM03282-AS AM03298-SS AD00603 AM01272-AS AM01205-SS AD02152 AM03259-AS AM03225-SS AD02532 AM03283-AS AM03298-SS AD00604 AM01273-AS AM01206-SS AD02153 AM03259-AS AM03226-SS AD02533 AM03284-AS AM03298-SS AD00605 AM01274-AS AM01207-SS AD02154 AM03259-AS AM03227-SS AD02534 AM03300-AS AM03298-SS AD00606 AM01275-AS AM01208-SS AD02155 AM03259-AS AM03228-SS AD02535 AM03301-AS AM03298-SS AD00607 AM01276-AS AM01209-SS AD02156 AM03259-AS AM03229-SS AD02536 AM03107-AS AM03299-SS AD00608 AM01277-AS AM01210-SS AD02157 AM03259-AS AM03230-SS AD02537 AM03279-AS AM03299-SS AD00609 AM01278-AS AM01211-SS AD02158 AM03259-AS AM03231-SS AD02538 AM03280-AS AM03299-SS AD00610 AM01279-AS AM01212-SS AD02159 AM03259-AS AM03232-SS AD02539 AM03281-AS AM03299-SS AD00611 AM01280-AS AM01213-SS AD02160 AM03259-AS AM03233-SS AD02540 AM03282-AS AM03299-SS AD00612 AM01281-AS AM01214-SS AD02161 AM03259-AS AM03234-SS AD02541 AM03283-AS AM03299-SS AD00613 AM01282-AS AM01215-SS AD02162 AM03259-AS AM03235-SS AD02542 AM03284-AS AM03299-SS AD00614 AM01283-AS AM01216-SS AD02163 AM03259-AS AM03236-SS AD02543 AM03300-AS AM03299-SS AD00615 AM01284-AS AM01217-SS AD02164 AM03259-AS AM03237-SS AD02544 AM03301-AS AM03299-SS AD00616 AM01285-AS AM01218-SS AD02165 AM03260-AS AM03220-SS AD02545 AM03301-AS AM03277-SS AD00617 AM01286-AS AM01219-SS AD02166 AM03260-AS AM03221-SS AD02546 AM03107-AS AM03275-SS AD00618 AM01287-AS AM01220-SS AD02167 AM03260-AS AM03222-SS AD02547 AM03107-AS AM03276-SS AD00619 AM01288-AS AM01221-SS AD02168 AM03260-AS AM03223-SS AD02548 AM03107-AS AM03277-SS AD00620 AM01289-AS AM01222-SS AD02169 AM03260-AS AM03224-SS AD02549 AM03107-AS AM03278-SS AD00621 AM01290-AS AM01223-SS AD02170 AM03260-AS AM03225-SS AD02550 AM03107-AS AM03287-SS AD00622 AM01291-AS AM01224-SS AD02171 AM03260-AS AM03226-SS AD02551 AM03107-AS AM03288-SS AD00623 AM01292-AS AM01225-SS AD02172 AM03260-AS AM03227-SS AD02552 AM03107-AS AM03289-SS AD00624 AM01293-AS AM01226-SS AD02173 AM03260-AS AM03228-SS AD02553 AM03107-AS AM03290-SS AD00625 AM01294-AS AM01227-SS AD02174 AM03260-AS AM03229-SS AD02554 AM03279-AS AM02537-SS AD00626 AM01295-AS AM01228-SS AD02175 AM03260-AS AM03230-SS AD02555 AM03280-AS AM02537-SS AD00627 AM01296-AS AM01229-SS AD02176 AM03260-AS AM03231-SS AD02556 AM03281-AS AM02537-SS AD00628 AM01297-AS AM01230-SS AD02177 AM03260-AS AM03232-SS AD02557 AM03282-AS AM02537-SS AD00629 AM01298-AS AM01231-SS AD02178 AM03260-AS AM03233-SS AD02558 AM03283-AS AM02537-SS AD00630 AM01299-AS AM01232-SS AD02179 AM03260-AS AM03234-SS AD02559 AM03284-AS AM02537-SS AD00631 AM01300-AS AM01233-SS AD02180 AM03260-AS AM03235-SS AD02560 AM03300-AS AM02537-SS AD00632 AM01301-AS AM01234-SS AD02181 AM03260-AS AM03236-SS AD02561 AM03301-AS AM02537-SS AD00633 AM01302-AS AM01235-SS AD02182 AM03260-AS AM03237-SS AD02609 AM03375-AS AM03277-SS AD00634 AM01303-AS AM01236-SS AD02183 AM03261-AS AM03220-SS AD02610 AM03376-AS AM03277-SS AD00635 AM01304-AS AM01237-SS AD02184 AM03261-AS AM03221-SS AD02611 AM03375-AS AM03278-SS AD00636 AM01305-AS AM01238-SS AD02185 AM03261-AS AM03222-SS AD02612 AM03376-AS AM03278-SS AD00637 AM01306-AS AM01239-SS AD02186 AM03261-AS AM03223-SS AD02613 AM03375-AS AM03289-SS AD01068 AM01796-AS AM01795-SS AD02187 AM03261-AS AM03224-SS AD02614 AM03376-AS AM03289-SS AD01069 AM01798-AS AM01797-SS AD02188 AM03261-AS AM03225-SS AD02615 AM03377-AS AM02941-SS AD01070 AM01800-AS AM01799-SS AD02189 AM03261-AS AM03226-SS AD02616 AM03259-AS AM02941-SS AD01071 AM01802-AS AM01801-SS AD02190 AM03261-AS AM03227-SS AD02617 AM03377-AS AM02942-SS AD01072 AM01804-AS AM01803-SS AD02191 AM03261-AS AM03228-SS AD02618 AM03259-AS AM02942-SS AD01073 AM01806-AS AM01805-SS AD02192 AM03261-AS AM03229-SS AD02619 AM03377-AS AM03243-SS AD01074 AM01808-AS AM01807-SS AD02193 AM03261-AS AM03230-SS AD02620 AM03259-AS AM03243-SS AD01075 AM01810-AS AM01809-SS AD02194 AM03261-AS AM03231-SS AD02662 AM02860-AS AM03424-SS AD01076 AM01812-AS AM01811-SS AD02195 AM03261-AS AM03232-SS AD02663 AM02860-AS AM03425-SS AD01077 AM01814-AS AM01813-SS AD02196 AM03261-AS AM03233-SS AD02664 AM03427-AS AM03426-SS AD01078 AM01816-AS AM01815-SS AD02197 AM03261-AS AM03234-SS AD02682 AM02775-AS AM03457-SS AD01079 AM01818-AS AM01817-SS AD02198 AM03261-AS AM03235-SS AD02683 AM02776-AS AM03458-SS AD01184 AM02003-AS AM02006-SS AD02199 AM03261-AS AM03236-SS AD02684 AM02783-AS AM03459-SS AD01185 AM02004-AS AM02006-SS AD02200 AM03261-AS AM03237-SS AD02685 AM02785-AS AM03460-SS AD01186 AM02005-AS AM02006-SS AD02201 AM03262-AS AM03220-SS AD02686 AM02788-AS AM03461-SS AD01187 AM02007-AS AM02010-SS AD02202 AM03262-AS AM03221-SS AD02687 AM02791-AS AM03462-SS AD01188 AM02008-AS AM02010-SS AD02203 AM03262-AS AM03222-SS AD02696 AM02860-AS AM03243-SS AD01189 AM02009-AS AM02010-SS AD02204 AM03262-AS AM03223-SS AD02697 AM03107-AS AM03277-SS AD01190 AM02011-AS AM02014-SS AD02205 AM03262-AS AM03224-SS AD02698 AM03107-AS AM03278-SS AD01191 AM02012-AS AM02014-SS AD02206 AM03262-AS AM03225-SS AD02699 AM03107-AS AM03289-SS AD01192 AM02013-AS AM02014-SS AD02207 AM03262-AS AM03226-SS AD02710 AM03486-AS AM03489-SS AD01193 AM02015-AS AM02018-SS AD02208 AM03262-AS AM03227-SS AD02711 AM03487-AS AM03489-SS AD01194 AM02016-AS AM02018-SS AD02209 AM03262-AS AM03228-SS AD02712 AM03488-AS AM03489-SS AD01195 AM02017-AS AM02018-SS AD02210 AM03262-AS AM03229-SS AD02713 AM02860-AS AM03489-SS AD01196 AM02019-AS AM02022-SS AD02211 AM03262-AS AM03230-SS AD02714 AM03490-AS AM03492-SS AD01197 AM02020-AS AM02022-SS AD02212 AM03262-AS AM03231-SS AD02715 AM03491-AS AM03492-SS AD01198 AM02021-AS AM02022-SS AD02213 AM03262-AS AM03232-SS AD02716 AM02531-AS AM03492-SS AD01199 AM02023-AS AM02026-SS AD02214 AM03262-AS AM03233-SS AD02717 AM03107-AS AM03492-SS AD01200 AM02024-AS AM02026-SS AD02215 AM03262-AS AM03234-SS AD02745 AM03107-AS AM03544-SS AD01201 AM02025-AS AM02026-SS AD02216 AM03262-AS AM03235-SS AD02746 AM03283-AS AM03544-SS AD01202 AM02027-AS AM02030-SS AD02217 AM03262-AS AM03236-SS AD02747 AM03300-AS AM03544-SS AD01203 AM02028-AS AM02030-SS AD02218 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AM03066-AS AM03061-SS AD02385 AM03272-AS AM03224-SS AD03577 AM04544-AS AM04543-SS AD01920 AM03067-AS AM03061-SS AD02386 AM03272-AS AM03225-SS AD03578 AM04545-AS AM04500-SS AD01921 AM03068-AS AM03061-SS AD02387 AM03272-AS AM03226-SS AD03579 AM04546-AS AM04500-SS AD01922 AM03069-AS AM03061-SS AD02388 AM03272-AS AM03227-SS AD03603 AM04582-AS AM04578-SS AD01923 AM03070-AS AM03061-SS AD02389 AM03272-AS AM03228-SS AD03604 AM04583-AS AM04578-SS AD01924 AM03065-AS AM03062-SS AD02390 AM03272-AS AM03229-SS AD03605 AM04584-AS AM04578-SS AD01925 AM03066-AS AM03062-SS AD02391 AM03272-AS AM03230-SS AD03606 AM04585-AS AM04578-SS AD01926 AM03067-AS AM03062-SS AD02392 AM03272-AS AM03231-SS AD03607 AM04586-AS AM04578-SS AD01927 AM03068-AS AM03062-SS AD02393 AM03272-AS AM03232-SS AD03608 AM04587-AS AM04578-SS AD01928 AM03069-AS AM03062-SS AD02394 AM03272-AS AM03233-SS AD03609 AM04584-AS AM04588-SS AD01929 AM03070-AS AM03062-SS AD02395 AM03272-AS AM03234-SS AD03610 AM04584-AS AM04579-SS AD01930 AM03065-AS AM03037-SS AD02396 AM03272-AS AM03235-SS AD03611 AM04584-AS AM04580-SS AD01931 AM03066-AS AM03037-SS AD02397 AM03272-AS AM03236-SS AD03612 AM04584-AS AM04581-SS AD01932 AM03067-AS AM03037-SS AD02398 AM03272-AS AM03237-SS AD03627 AM04609-AS AM03970-SS AD01933 AM03068-AS AM03037-SS AD02399 AM03273-AS AM03220-SS AD03628 AM04610-AS AM03970-SS AD01934 AM03069-AS AM03037-SS AD02400 AM03273-AS AM03221-SS AD03629 AM03972-AS AM04611-SS AD01935 AM03070-AS AM03037-SS AD02401 AM03273-AS AM03222-SS AD03630 AM03972-AS AM04612-SS AD01936 AM03065-AS AM03064-SS AD02402 AM03273-AS AM03223-SS AD03668 AM04501-AS AM04500-SS AD01937 AM03066-AS AM03064-SS AD02403 AM03273-AS AM03224-SS AD03671 AM04677-AS AM04669-SS AD01938 AM03067-AS AM03064-SS AD02404 AM03273-AS AM03225-SS AD03672 AM04678-AS AM04670-SS AD01939 AM03068-AS AM03064-SS AD02405 AM03273-AS AM03226-SS AD03673 AM04679-AS AM04671-SS AD01940 AM03069-AS AM03064-SS AD02406 AM03273-AS AM03227-SS AD03674 AM04680-AS AM04672-SS AD01941 AM03070-AS AM03064-SS AD02407 AM03273-AS AM03228-SS AD03675 AM04681-AS AM04673-SS AD01976 AM03119-AS AM02540-SS AD02408 AM03273-AS AM03229-SS AD03676 AM02860-AS AM04674-SS AD01977 AM03120-AS AM02540-SS AD02409 AM03273-AS AM03230-SS AD03677 AM02860-AS AM04675-SS AD01978 AM03121-AS AM02540-SS AD02410 AM03273-AS AM03231-SS AD03678 AM02860-AS AM04676-SS AD01979 AM02857-AS AM03122-SS AD02411 AM03273-AS AM03232-SS AD03705 AM04501-AS AM04726-SS AD01980 AM02857-AS AM03123-SS AD02412 AM03273-AS AM03233-SS AD03706 AM04501-AS AM04727-SS AD01981 AM03119-AS AM03122-SS AD02413 AM03273-AS AM03234-SS AD03707 AM04501-AS AM04728-SS AD01982 AM02857-AS AM03124-SS AD02414 AM03273-AS AM03235-SS AD03708 AM04544-AS AM04729-SS AD01983 AM03107-AS AM02537-SS AD02415 AM03273-AS AM03236-SS AD03713 AM04733-AS AM04138-SS AD01984 AM03108-AS AM02537-SS AD02416 AM03273-AS AM03237-SS AD03714 AM04734-AS AM04138-SS AD01985 AM03107-AS AM03125-SS AD02417 AM03274-AS AM03220-SS AD03715 AM04735-AS AM04138-SS AD01986 AM03107-AS AM03126-SS AD02418 AM03274-AS AM03221-SS AD03716 AM04736-AS AM04138-SS AD01987 AM03127-AS AM02537-SS AD02419 AM03274-AS AM03222-SS AD03717 AM02860-AS AM04737-SS AD01988 AM03129-AS AM03128-SS AD02420 AM03274-AS AM03223-SS AD03720 AM03884-AS AM04741-SS AD01989 AM03130-AS AM02540-SS AD02421 AM03274-AS AM03224-SS AD03721 AM03972-AS AM04742-SS AD01990 AM03131-AS AM02540-SS AD02422 AM03274-AS AM03225-SS AD03722 AM03972-AS AM04743-SS AD02001 AM02860-AS AM02942-SS AD02423 AM03274-AS AM03226-SS AD03723 AM03972-AS AM04744-SS AD02002 AM02857-AS AM03144-SS AD02424 AM03274-AS AM03227-SS AD03760 AM04805-AS AM04803-SS AD02003 AM03149-AS AM02540-SS AD02425 AM03274-AS AM03228-SS AD03761 AM04501-AS AM04804-SS AD02004 AM03149-AS AM02941-SS AD02426 AM03274-AS AM03229-SS AD03762 AM04805-AS AM04807-SS AD02005 AM03149-AS AM02942-SS AD02427 AM03274-AS AM03230-SS AD03763 AM03884-AS AM04729-SS AD02006 AM03150-AS AM02540-SS AD02428 AM03274-AS AM03231-SS AD03764 AM03884-AS AM04806-SS AD02007 AM03150-AS AM02941-SS AD02429 AM03274-AS AM03232-SS AD03765 AM04501-AS AM04611-SS AD02008 AM03150-AS AM02942-SS AD02430 AM03274-AS AM03233-SS AD03766 AM04501-AS AM04808-SS AD02009 AM03151-AS AM02540-SS AD02431 AM03274-AS AM03234-SS AD03767 AM04501-AS AM04809-SS AD02010 AM03151-AS AM02941-SS AD02432 AM03274-AS AM03235-SS AD03768 AM04501-AS AM04810-SS AD02011 AM03151-AS AM02942-SS AD02433 AM03274-AS AM03236-SS AD03769 AM04501-AS AM04811-SS AD02075 AM03255-AS AM03220-SS AD02434 AM03274-AS AM03237-SS AD03770 AM04501-AS AM04812-SS AD02076 AM03255-AS AM03221-SS AD02435 AM03255-AS AM03238-SS AD03771 AM02860-AS AM04813-SS AD02077 AM03255-AS AM03222-SS AD02436 AM03256-AS AM03238-SS AD03801 AM04821-AS AM04816-SS AD02078 AM03255-AS AM03223-SS AD02437 AM03255-AS AM03240-SS AD03802 AM04822-AS AM04817-SS AD02079 AM03255-AS AM03224-SS AD02438 AM03256-AS AM03240-SS AD03803 AM04823-AS AM04816-SS AD02080 AM03255-AS AM03225-SS AD02439 AM03255-AS AM02942-SS AD03804 AM04821-AS AM04835-SS AD02081 AM03255-AS AM03226-SS AD02440 AM03256-AS AM02942-SS AD03805 AM04824-AS AM04819-SS AD02082 AM03255-AS AM03227-SS AD02462 AM02857-AS AM03330-SS AD03806 AM04824-AS AM04820-SS AD02083 AM03255-AS AM03228-SS AD02463 AM03331-AS AM01223-SS AD03841 AM04871-AS AM04862-SS AD02084 AM03255-AS AM03229-SS AD02464 AM03107-AS AM03291-SS AD03842 AM02860-AS AM04863-SS AD02085 AM03255-AS AM03230-SS AD02465 AM03279-AS AM03291-SS AD03843 AM04872-AS AM04138-SS AD02086 AM03255-AS AM03231-SS AD02466 AM03280-AS AM03291-SS AD03844 AM04539-AS AM04864-SS AD02087 AM03255-AS AM03232-SS AD02467 AM03281-AS AM03291-SS AD03845 AM03300-AS AM04865-SS AD02088 AM03255-AS AM03233-SS AD02468 AM03282-AS AM03291-SS AD03846 AM04873-AS AM04412-SS AD02089 AM03255-AS AM03234-SS AD02469 AM03283-AS AM03291-SS AD03847 AM04874-AS AM04866-SS AD02090 AM03255-AS AM03235-SS AD02470 AM03284-AS AM03291-SS AD03848 AM04874-AS AM04867-SS AD02091 AM03255-AS AM03236-SS AD02471 AM03300-AS AM03291-SS AD03849 AM04875-AS AM04867-SS AD02092 AM03255-AS AM03237-SS AD02472 AM03301-AS AM03291-SS AD03850 AM04876-AS AM04866-SS AD02093 AM03256-AS AM03220-SS AD02473 AM03107-AS AM03292-SS AD03851 AM04877-AS AM04866-SS AD02094 AM03256-AS AM03221-SS AD02474 AM03279-AS AM03292-SS AD03852 AM04877-AS AM04867-SS AD02095 AM03256-AS AM03222-SS AD02475 AM03280-AS AM03292-SS AD03853 AM04874-AS AM04868-SS AD02096 AM03256-AS AM03223-SS AD02476 AM03281-AS AM03292-SS AD03854 AM04874-AS AM04869-SS AD02097 AM03256-AS AM03224-SS AD02477 AM03282-AS AM03292-SS AD03855 AM04875-AS AM04869-SS AD02098 AM03256-AS AM03225-SS AD02478 AM03283-AS AM03292-SS AD03856 AM04874-AS AM04870-SS AD02099 AM03256-AS AM03226-SS AD02479 AM03284-AS AM03292-SS AD03857 AM03972-AS AM04808-SS AD02100 AM03256-AS AM03227-SS AD02480 AM03300-AS AM03292-SS AD03858 AM03972-AS AM04811-SS AD02101 AM03256-AS AM03228-SS AD02481 AM03301-AS AM03292-SS AD03859 AM04822-AS AM04819-SS AD02102 AM03256-AS AM03229-SS AD02482 AM03107-AS AM03293-SS AD03860 AM04878-AS AM04819-SS AD02103 AM03256-AS AM03230-SS AD02483 AM03279-AS AM03293-SS AD03861 AM04878-AS AM04820-SS AD02104 AM03256-AS AM03231-SS AD02484 AM03280-AS AM03293-SS AD03862 AM04879-AS AM04138-SS AD02105 AM03256-AS AM03232-SS AD02485 AM03281-AS AM03293-SS AD03863 AM04879-AS AM04863-SS AD02106 AM03256-AS AM03233-SS AD02486 AM03282-AS AM03293-SS AD03864 AM04880-AS AM04138-SS AD02107 AM03256-AS AM03234-SS AD02487 AM03283-AS AM03293-SS AD03920 AM04969-AS AM04138-SS AD02108 AM03256-AS AM03235-SS AD02488 AM03284-AS AM03293-SS AD03921 AM04970-AS AM04412-SS AD02109 AM03256-AS AM03236-SS AD02489 AM03300-AS AM03293-SS AD03922 AM04971-AS AM04867-SS AD02110 AM03256-AS AM03237-SS AD02490 AM03301-AS AM03293-SS AD03923 AM04971-AS AM04869-SS AD02111 AM03257-AS AM03220-SS AD02491 AM03107-AS AM03294-SS AD03924 AM04972-AS AM04820-SS AD02112 AM03257-AS AM03221-SS AD02492 AM03279-AS AM03294-SS AD03925 AM04972-AS AM04819-SS AD02113 AM03257-AS AM03222-SS AD02493 AM03280-AS AM03294-SS AD03931 AM04979-AS AM04978-SS AD02114 AM03257-AS AM03223-SS AD02494 AM03281-AS AM03294-SS AD03932 AM04979-AS AM04811-SS AD02115 AM03257-AS AM03224-SS AD02495 AM03282-AS AM03294-SS AD03933 AM04979-AS AM04869-SS AD02116 AM03257-AS AM03225-SS AD02496 AM03283-AS AM03294-SS AD04017 AM03300-AS AM05070-SS AD02117 AM03257-AS AM03226-SS AD02497 AM03284-AS AM03294-SS AD04018 AM03972-AS AM05072-SS AD02118 AM03257-AS AM03227-SS AD02498 AM03300-AS AM03294-SS AD04017 AM03300-AS AM05070-SS AD02119 AM03257-AS AM03228-SS AD02499 AM03301-AS AM03294-SS AD04018 AM03972-AS AM05072-SS AD04170 AM03972-AS AM05341-SS AD04171 AM04877-AS AM05342-SS AD04110 AM04875-AS AM04866-SS AD04263 AM04879-AS AM05489-SS AD04272 AM04979-AS AM05499-SS AD04281 AM05496-AS AM04412-SS AD04264 AM05490-AS AM04416-SS AD04273 AM03972-AS AM05494-SS AD04282 AM04874-AS AM05503-SS AD04265 AM05490-AS AM05491-SS AD04274 AM05498-AS AM05494-SS AD04283 AM04874-AS AM05502-SS AD04266 AM05492-AS AM04496-SS AD04275 AM04979-AS AM05494-SS AD04284 AM04874-AS AM05506-SS AD04267 AM05493-AS AM04496-SS AD04276 AM03972-AS AM05501-SS AD04285 AM04877-AS AM05503-SS AD04268 AM05498-AS AM04496-SS AD04277 AM05498-AS AM05501-SS AD04286 AM05497-AS AM05502-SS AD04269 AM04979-AS AM04496-SS AD04278 AM04979-AS AM05501-SS AD04287 AM05497-AS AM05506-SS AD04270 AM03972-AS AM05499-SS AD04279 AM03300-AS AM05500-SS AD04288 AM04874-AS AM05504-SS AD04271 AM05498-AS AM05499-SS AD04280 AM05495-AS AM04412-SS AD04289 AM04874-AS AM05505-SS

TABLE 3B LPA RNAi agent duplexes with Duplex ID numbers. Antisense Sense Strand Duplex ID Strand ID ID SD0001 1533-AS00 1533-SS00 SD0002 1533-AS01 1533-SS00 SD0003 1533-AS02 1533-SS00 SD0004 1533-AS03 1533-SS00 SD0005 1533-AS04 1533-SS00 SD0006 1533-AS05 1533-SS00 SD0007 1533-AS06 1533-SS00 SD0008 1533-AS07 1533-SS00 SD0009 1533-AS08 1533-SS00 SD0010 1533-AS09 1533-SS00 SD0011 1533-AS10 1533-SS00 SD0012 1533-AS11 1533-SS00 SD0013 1533-AS12 1533-SS00 SD0014 1533-AS13 1533-SS00 SD0015 1533-AS14 1533-SS00 SD0016 1533-AS00 1533-SS01 SD0017 1533-AS01 1533-SS01 SD0018 1533-AS02 1533-SS01 SD0019 1533-AS03 1533-SS01 SD0020 1533-AS04 1533-SS01 SD0021 1533-AS05 1533-SS01 SD0022 1533-AS06 1533-SS01 SD0023 1533-AS07 1533-SS01 SD0024 1533-AS08 1533-SS01 SD0025 1533-AS09 1533-SS01 SD0026 1533-AS10 1533-SS01 SD0027 1533-AS11 1533-SS01 SD0028 1533-AS12 1533-SS01 SD0029 1533-AS13 1533-SS01 SD0030 1533-AS14 1533-SS01 SD0031 1533-AS00 1533-SS02 SD0032 1533-AS01 1533-SS02 SD0033 1533-AS02 1533-SS02 SD0034 1533-AS03 1533-SS02 SD0035 1533-AS04 1533-SS02 SD0036 1533-AS05 1533-SS02 SD0037 1533-AS06 1533-SS02 SD0038 1533-AS07 1533-SS02 SD0039 1533-AS08 1533-SS02 SD0040 1533-AS09 1533-SS02 SD0041 1533-AS10 1533-SS02 SD0042 1533-AS11 1533-SS02 SD0043 1533-AS12 1533-SS02 SD0044 1533-AS13 1533-SS02 SD0045 1533-AS14 1533-SS02 SD0046 1533-AS00 1533-SS03 SD0047 1533-AS01 1533-SS03 SD0048 1533-AS02 1533-SS03 SD0049 1533-AS03 1533-SS03 SD0050 1533-AS04 1533-SS03 SD0051 1533-AS05 1533-SS03 SD0052 1533-AS06 1533-SS03 SD0053 1533-AS07 1533-SS03 SD0054 1533-AS08 1533-SS03 SD0055 1533-AS09 1533-SS03 SD0056 1533-AS10 1533-SS03 SD0057 1533-AS11 1533-SS03 SD0058 1533-AS12 1533-SS03 SD0059 1533-AS13 1533-SS03 SD0060 1533-AS14 1533-SS03 SD0061 1533-AS00 1533-SS04 SD0062 1533-AS01 1533-SS04 SD0063 1533-AS02 1533-SS04 SD0064 1533-AS03 1533-SS04 SD0065 1533-AS04 1533-SS04 SD0066 1533-AS05 1533-SS04 SD0067 1533-AS06 1533-SS04 SD0068 1533-AS07 1533-SS04 SD0069 1533-AS08 1533-SS04 SD0070 1533-AS09 1533-SS04 SD0071 1533-AS10 1533-SS04 SD0072 1533-AS11 1533-SS04 SD0073 1533-AS12 1533-SS04 SD0074 1533-AS13 1533-SS04 SD0075 1533-AS14 1533-SS04 SD0076 1533-AS00 1533-SS05 SD0077 1533-AS01 1533-SS05 SD0078 1533-AS02 1533-SS05 SD0079 1533-AS03 1533-SS05 SD0080 1533-AS04 1533-SS05 SD0081 1533-AS05 1533-SS05 SD0082 1533-AS06 1533-SS05 SD0083 1533-AS07 1533-SS05 SD0084 1533-AS08 1533-SS05 SD0085 1533-AS09 1533-SS05 SD0086 1533-AS10 1533-SS05 SD0087 1533-AS11 1533-SS05 SD0088 1533-AS12 1533-SS05 SD0089 1533-AS13 1533-SS05 SD0090 1533-AS14 1533-SS05 SD0091 1533-AS00 1533-SS06 SD0092 1533-AS01 1533-SS06 SD0093 1533-AS02 1533-SS06 SD0094 1533-AS03 1533-SS06 SD0095 1533-AS04 1533-SS06 SD0096 1533-AS05 1533-SS06 SD0097 1533-AS06 1533-SS06 SD0098 1533-AS07 1533-SS06 SD0099 1533-AS08 1533-SS06 SD0100 1533-AS09 1533-SS06 SD0101 1533-AS10 1533-SS06 SD0102 1533-AS11 1533-SS06 SD0103 1533-AS12 1533-SS06 SD0104 1533-AS13 1533-SS06 SD0105 1533-AS14 1533-SS06 SD0106 1533-AS00 1533-SS07 SD0107 1533-AS01 1533-SS07 SD0108 1533-AS02 1533-SS07 SD0109 1533-AS03 1533-SS07 SD0110 1533-AS04 1533-SS07 SD0111 1533-AS05 1533-SS07 SD0112 1533-AS06 1533-SS07 SD0113 1533-AS07 1533-SS07 SD0114 1533-AS08 1533-SS07 SD0115 1533-AS09 1533-SS07 SD0116 1533-AS10 1533-SS07 SD0117 1533-AS11 1533-SS07 SD0118 1533-AS12 1533-SS07 SD0119 1533-AS13 1533-SS07 SD0120 1533-AS14 1533-SS07 SD0121 1533-AS00 1533-SS08 SD0122 1533-AS01 1533-SS08 SD0123 1533-AS02 1533-SS08 SD0124 1533-AS03 1533-SS08 SD0125 1533-AS04 1533-SS08 SD0126 1533-AS05 1533-SS08 SD0127 1533-AS06 1533-SS08 SD0128 1533-AS07 1533-SS08 SD0129 1533-AS08 1533-SS08 SD0130 1533-AS09 1533-SS08 SD0131 1533-AS10 1533-SS08 SD0132 1533-AS11 1533-SS08 SD0133 1533-AS12 1533-SS08 SD0134 1533-AS13 1533-SS08 SD0135 1533-AS14 1533-SS08 SD0136 1533-AS00 1533-SS09 SD0137 1533-AS01 1533-SS09 SD0138 1533-AS02 1533-SS09 SD0139 1533-AS03 1533-SS09 SD0140 1533-AS04 1533-SS09 SD0141 1533-AS05 1533-SS09 SD0142 1533-AS06 1533-SS09 SD0143 1533-AS07 1533-SS09 SD0144 1533-AS08 1533-SS09 SD0145 1533-AS09 1533-SS09 SD0146 1533-AS10 1533-SS09 SD0147 1533-AS11 1533-SS09 SD0148 1533-AS12 1533-SS09 SD0149 1533-AS13 1533-SS09 SD0150 1533-AS14 1533-SS09 SD0151 1533-AS00 1533-SS01 SD0152 1533-AS01 1533-SS01 SD0153 1533-AS02 1533-SS01 SD0154 1533-AS03 1533-SS01 SD0155 1533-AS04 1533-SS01 SD0156 1533-AS05 1533-SS01 SD0157 1533-AS06 1533-SS01 SD0158 1533-AS07 1533-SS01 SD0159 1533-AS08 1533-SS01 SD0160 1533-AS09 1533-SS01 SD0161 1533-AS10 1533-SS01 SD0162 1533-AS11 1533-SS01 SD0163 1533-AS12 1533-SS01 SD0164 1533-AS13 1533-SS01 SD0165 1533-AS14 1533-SS01 SD0166 1533-AS00 1533-SS01 SD0167 1533-AS01 1533-SS01 SD0168 1533-AS02 1533-SS01 SD0169 1533-AS03 1533-SS01 SD0170 1533-AS04 1533-SS01 SD0171 1533-AS05 1533-SS01 SD0172 1533-AS06 1533-SS01 SD0173 1533-AS07 1533-SS01 SD0174 1533-AS08 1533-SS01 SD0175 1533-AS09 1533-SS01 SD0176 1533-AS10 1533-SS01 SD0177 1533-AS11 1533-SS01 SD0178 1533-AS12 1533-SS01 SD0179 1533-AS13 1533-SS01 SD0180 1533-AS14 1533-SS01 SD0181 1533-AS00 1533-SS02 SD0182 1533-AS01 1533-SS02 SD0183 1533-AS02 1533-SS02 SD0184 1533-AS03 1533-SS02 SD0185 1533-AS04 1533-SS02 SD0186 1533-AS05 1533-SS02 SD0187 1533-AS06 1533-SS02 SD0188 1533-AS07 1533-SS02 SD0189 1533-AS08 1533-SS02 SD0190 1533-AS09 1533-SS02 SD0191 1533-AS10 1533-SS02 SD0192 1533-AS11 1533-SS02 SD0193 1533-AS12 1533-SS02 SD0194 1533-AS13 1533-SS02 SD0195 1533-AS14 1533-SS02 SD0196 1533-AS00 1533-CfinSS SD0197 1533-AS01 1533-CfinSS SD0198 1533-AS02 1533-CfinSS SD0199 1533-AS03 1533-CfinSS SD0200 1533-AS04 1533-CfinSS SD0201 1533-AS05 1533-CfinSS SD0202 1533-AS06 1533-CfinSS SD0203 1533-AS07 1533-CfinSS SD0204 1533-AS08 1533-CfinSS SD0205 1533-AS09 1533-CfinSS SD0206 1533-AS10 1533-CfinSS SD0207 1533-AS11 1533-CfinSS SD0208 1533-AS12 1533-CfinSS SD0209 1533-AS13 1533-CfinSS SD0210 1533-AS14 1533-CfinSS SD0211 1533-CfinAS 1533-SS00 SD0212 1533-CfinAS 1533-SS01 SD0213 1533-CfinAS 1533-SS02 SD0214 1533-CfinAS 1533-SS03 SD0215 1533-CfinAS 1533-SS04 SD0216 1533-CfinAS 1533-SS05 SD0217 1533-CfinAS 1533-SS06 SD0218 1533-CfinAS 1533-SS07 SD0219 1533-CfinAS 1533-SS08 SD0220 1533-CfinAS 1533-SS09 SD0221 1533-CfinAS 1533-SS10 SD0222 1533-CfinAS 1533-SS11 SD0223 1533-CfinAS 1533-SS12 SD0224 1533-CfinAS 1533-SS13 SD0225 1533-CfinAS 1533-SS14 SD0226 1533-CfinAS 1533-SS15 SD0227 1533-CfinAS 1533-SS16 SD0228 1533-CfinAS 1533-SS17 SD0229 1533-CfinAS 1533-SS18 SD0230 1533-CfinAS 1533-SS19 SD0231 1533-CfinAS 1533-SS20 SD0232 1533-AS00 1533-SS12 SD0233 1533-AS01 1533-SS12 SD0234 1533-AS02 1533-SS12 SD0235 1533-AS03 1533-SS12 SD0236 1533-AS04 1533-SS12 SD0237 1533-AS05 1533-SS12 SD0238 1533-AS06 1533-SS12 SD0239 1533-AS07 1533-SS12 SD0240 1533-AS08 1533-SS12 SD0241 1533-AS09 1533-SS12 SD0242 1533-AS10 1533-SS12 SD0243 1533-AS11 1533-SS12 SD0244 1533-AS12 1533-SS12 SD0245 1533-AS13 1533-SS12 SD0246 1533-AS14 1533-SS12 SD0247 1533-AS00 1533-SS13 SD0248 1533-AS01 1533-SS13 SD0249 1533-AS02 1533-SS13 SD0250 1533-AS03 1533-SS13 SD0251 1533-AS04 1533-SS13 SD0252 1533-AS05 1533-SS13 SD0253 1533-AS06 1533-SS13 SD0254 1533-AS07 1533-SS13 SD0255 1533-AS08 1533-SS13 SD0256 1533-AS09 1533-SS13 SD0257 1533-AS10 1533-SS13 SD0258 1533-AS11 1533-SS13 SD0259 1533-AS12 1533-SS13 SD0260 1533-AS13 1533-SS13 SD0261 1533-AS14 1533-SS13 SD0262 1533-AS00 1533-SS14 SD0263 1533-AS01 1533-SS14 SD0264 1533-AS02 1533-SS14 SD0265 1533-AS03 1533-SS14 SD0266 1533-AS04 1533-SS14 SD0267 1533-AS05 1533-SS14 SD0268 1533-AS06 1533-SS14 SD0269 1533-AS07 1533-SS14 SD0270 1533-AS08 1533-SS14 SD0271 1533-AS09 1533-SS14 SD0272 1533-AS10 1533-SS14 SD0273 1533-AS11 1533-SS14 SD0274 1533-AS12 1533-SS14 SD0275 1533-AS13 1533-SS14 SD0276 1533-AS14 1533-SS14 SD0277 1533-AS00 1533-SS15 SD0278 1533-AS01 1533-SS15 SD0279 1533-AS02 1533-SS15 SD0280 1533-AS03 1533-SS15 SD0281 1533-AS04 1533-SS15 SD0282 1533-AS05 1533-SS15 SD0283 1533-AS06 1533-SS15 SD0284 1533-AS07 1533-SS15 SD0285 1533-AS08 1533-SS15 SD0286 1533-AS09 1533-SS15 SD0287 1533-AS10 1533-SS15 SD0288 1533-AS11 1533-SS15 SD0289 1533-AS12 1533-SS15 SD0290 1533-AS13 1533-SS15 SD0291 1533-AS14 1533-SS15 SD0292 1533-AS00 1533-SS16 SD0293 1533-AS01 1533-SS16 SD0294 1533-AS02 1533-SS16 SD0295 1533-AS03 1533-SS16 SD0296 1533-AS04 1533-SS16 SD0297 1533-AS05 1533-SS16 SD0298 1533-AS06 1533-SS16 SD0299 1533-AS07 1533-SS16 SD0300 1533-AS08 1533-SS16 SD0301 1533-AS09 1533-SS16 SD0302 1533-AS10 1533-SS16 SD0303 1533-AS11 1533-SS16 SD0304 1533-AS12 1533-SS16 SD0305 1533-AS13 1533-SS16 SD0306 1533-AS14 1533-SS16 SD0307 1533-AS00 1533-SS17 SD0308 1533-AS01 1533-SS17 SD0309 1533-AS02 1533-SS17 SD0310 1533-AS03 1533-SS17 SD0311 1533-AS04 1533-SS17 SD0312 1533-AS05 1533-SS17 SD0313 1533-AS06 1533-SS17 SD0314 1533-AS07 1533-SS17 SD0315 1533-AS08 1533-SS17 SD0316 1533-AS09 1533-SS17 SD0317 1533-AS10 1533-SS17 SD0318 1533-AS11 1533-SS17 SD0319 1533-AS12 1533-SS17 SD0320 1533-AS13 1533-SS17 SD0321 1533-AS14 1533-SS17 SD0322 1533-AS00 1533-SS18 SD0323 1533-AS01 1533-SS18 SD0324 1533-AS02 1533-SS18 SD0325 1533-AS03 1533-SS18 SD0326 1533-AS04 1533-SS18 SD0327 1533-AS05 1533-SS18 SD0328 1533-AS06 1533-SS18 SD0329 1533-AS07 1533-SS18 SD0330 1533-AS08 1533-SS18 SD0331 1533-AS09 1533-SS18 SD0332 1533-AS10 1533-SS18 SD0333 1533-AS11 1533-SS18 SD0334 1533-AS12 1533-SS18 SD0335 1533-AS13 1533-SS18 SD0336 1533-AS14 1533-SS18 SD0337 1533-AS00 1533-SS19 SD0338 1533-AS01 1533-SS19 SD0339 1533-AS02 1533-SS19 SD0340 1533-AS03 1533-SS19 SD0341 1533-AS04 1533-SS19 SD0342 1533-AS05 1533-SS19 SD0343 1533-AS06 1533-SS19 SD0344 1533-AS07 1533-SS19 SD0345 1533-AS08 1533-SS19 SD0346 1533-AS09 1533-SS19 SD0347 1533-AS10 1533-SS19 SD0348 1533-AS11 1533-SS19 SD0349 1533-AS12 1533-SS19 SD0350 1533-AS13 1533-SS19 SD0351 1533-AS14 1533-SS19 SD0352 1532-AS00 1532-SS00 SD0353 1532-AS01 1532-SS00 SD0354 1532-AS02 1532-SS00 SD0355 1532-AS03 1532-SS00 SD0356 1532-AS04 1532-SS00 SD0357 1532-AS05 1532-SS00 SD0358 1532-AS06 1532-SS00 SD0359 1532-AS07 1532-SS00 SD0360 1532-AS08 1532-SS00 SD0361 1532-AS09 1532-SS00 SD0362 1532-AS10 1532-SS00 SD0363 1532-AS11 1532-SS00 SD0364 1532-AS12 1532-SS00 SD0365 1532-AS13 1532-SS00 SD0366 1532-AS00 1532-SS01 SD0367 1532-AS01 1532-SS01 SD0368 1532-AS02 1532-SS01 SD0369 1532-AS03 1532-SS01 SD0370 1532-AS04 1532-SS01 SD0371 1532-AS05 1532-SS01 SD0372 1532-AS06 1532-SS01 SD0373 1532-AS07 1532-SS01 SD0374 1532-AS08 1532-SS01 SD0375 1532-AS09 1532-SS01 SD0376 1532-AS10 1532-SS01 SD0377 1532-AS11 1532-SS01 SD0378 1532-AS12 1532-SS01 SD0379 1532-AS13 1532-SS01 SD0380 1532-AS00 1532-SS02 SD0381 1532-AS01 1532-SS02 SD0382 1532-AS02 1532-SS02 SD0383 1532-AS03 1532-SS02 SD0384 1532-AS04 1532-SS02 SD0385 1532-AS05 1532-SS02 SD0386 1532-AS06 1532-SS02 SD0387 1532-AS07 1532-SS02 SD0388 1532-AS08 1532-SS02 SD0389 1532-AS09 1532-SS02 SD0390 1532-AS10 1532-SS02 SD0391 1532-AS11 1532-SS02 SD0392 1532-AS12 1532-SS02 SD0393 1532-AS13 1532-SS02 SD0394 1532-AS00 1532-SS03 SD0395 1532-AS01 1532-SS03 SD0396 1532-AS02 1532-SS03 SD0397 1532-AS03 1532-SS03 SD0398 1532-AS04 1532-SS03 SD0399 1532-AS05 1532-SS03 SD0400 1532-AS06 1532-SS03 SD0401 1532-AS07 1532-SS03 SD0402 1532-AS08 1532-SS03 SD0403 1532-AS09 1532-SS03 SD0404 1532-AS10 1532-SS03 SD0405 1532-AS11 1532-SS03 SD0406 1532-AS12 1532-SS03 SD0407 1532-AS13 1532-SS03 SD0408 1532-AS00 1532-SS04 SD0409 1532-AS01 1532-SS04 SD0410 1532-AS02 1532-SS04 SD0411 1532-AS03 1532-SS04 SD0412 1532-AS04 1532-SS04 SD0413 1532-AS05 1532-SS04 SD0414 1532-AS06 1532-SS04 SD0415 1532-AS07 1532-SS04 SD0416 1532-AS08 1532-SS04 SD0417 1532-AS09 1532-SS04 SD0418 1532-AS10 1532-SS04 SD0419 1532-AS11 1532-SS04 SD0420 1532-AS12 1532-SS04 SD0421 1532-AS13 1532-SS04 SD0422 1532-AS00 1532-SS05 SD0423 1532-AS01 1532-SS05 SD0424 1532-AS02 1532-SS05 SD0425 1532-AS03 1532-SS05 SD0426 1532-AS04 1532-SS05 SD0427 1532-AS05 1532-SS05 SD0428 1532-AS06 1532-SS05 SD0429 1532-AS07 1532-SS05 SD0430 1532-AS08 1532-SS05 SD0431 1532-AS09 1532-SS05 SD0432 1532-AS10 1532-SS05 SD0433 1532-AS11 1532-SS05 SD0434 1532-AS12 1532-SS05 SD0435 1532-AS13 1532-SS05 SD0436 1532-AS00 1532-SS06 SD0437 1532-AS01 1532-SS06 SD0438 1532-AS02 1532-SS06 SD0439 1532-AS03 1532-SS06 SD0440 1532-AS04 1532-SS06 SD0441 1532-AS05 1532-SS06 SD0442 1532-AS06 1532-SS06 SD0443 1532-AS07 1532-SS06 SD0444 1532-AS08 1532-SS06 SD0445 1532-AS09 1532-SS06 SD0446 1532-AS10 1532-SS06 SD0447 1532-AS11 1532-SS06 SD0448 1532-AS12 1532-SS06 SD0449 1532-AS13 1532-SS06 SD0450 1532-AS00 1532-SS07 SD0451 1532-AS01 1532-SS07 SD0452 1532-AS02 1532-SS07 SD0453 1532-AS03 1532-SS07 SD0454 1532-AS04 1532-SS07 SD0455 1532-AS05 1532-SS07 SD0456 1532-AS06 1532-SS07 SD0457 1532-AS07 1532-SS07 SD0458 1532-AS08 1532-SS07 SD0459 1532-AS09 1532-SS07 SD0460 1532-AS10 1532-SS07 SD0461 1532-AS11 1532-SS07 SD0462 1532-AS12 1532-SS07 SD0463 1532-AS13 1532-SS07 SD0464 1532-AS00 1532-SS08 SD0465 1532-AS01 1532-SS08 SD0466 1532-AS02 1532-SS08 SD0467 1532-AS03 1532-SS08 SD0468 1532-AS04 1532-SS08 SD0469 1532-AS05 1532-SS08 SD0470 1532-AS06 1532-SS08 SD0471 1532-AS07 1532-SS08 SD0472 1532-AS08 1532-SS08 SD0473 1532-AS09 1532-SS08 SD0474 1532-AS10 1532-SS08 SD0475 1532-AS11 1532-SS08 SD0476 1532-AS12 1532-SS08 SD0477 1532-AS13 1532-SS08 SD0478 1532-AS00 1532-SS09 SD0479 1532-AS01 1532-SS09 SD0480 1532-AS02 1532-SS09 SD0481 1532-AS03 1532-SS09 SD0482 1532-AS04 1532-SS09 SD0483 1532-AS05 1532-SS09 SD0484 1532-AS06 1532-SS09 SD0485 1532-AS07 1532-SS09 SD0486 1532-AS08 1532-SS09 SD0487 1532-AS09 1532-SS09 SD0488 1532-AS10 1532-SS09 SD0489 1532-AS11 1532-SS09 SD0490 1532-AS12 1532-SS09 SD0491 1532-AS13 1532-SS09 SD0492 1532-AS00 1532-SS10 SD0493 1532-AS01 1532-SS10 SD0494 1532-AS02 1532-SS10 SD0495 1532-AS03 1532-SS10 SD0496 1532-AS04 1532-SS10 SD0497 1532-AS05 1532-SS10 SD0498 1532-AS06 1532-SS10 SD0499 1532-AS07 1532-SS10 SD0500 1532-AS08 1532-SS10 SD0501 1532-AS09 1532-SS10 SD0502 1532-AS10 1532-SS10 SD0503 1532-AS11 1532-SS10 SD0504 1532-AS12 1532-SS10 SD0505 1532-AS13 1532-SS10 SD0506 1532-AS00 1532-SS11 SD0507 1532-AS01 1532-SS11 SD0508 1532-AS02 1532-SS11 SD0509 1532-AS03 1532-SS11 SD0510 1532-AS04 1532-SS11 SD0511 1532-AS05 1532-SS11 SD0512 1532-AS06 1532-SS11 SD0513 1532-AS07 1532-SS11 SD0514 1532-AS08 1532-SS11 SD0515 1532-AS09 1532-SS11 SD0516 1532-AS10 1532-SS11 SD0517 1532-AS11 1532-SS11 SD0518 1532-AS12 1532-SS11 SD0519 1532-AS13 1532-SS11 SD0520 1532-AS00 1532-SS12 SD0521 1532-AS01 1532-SS12 SD0522 1532-AS02 1532-SS12 SD0523 1532-AS03 1532-SS12 SD0524 1532-AS04 1532-SS12 SD0525 1532-AS05 1532-SS12 SD0526 1532-AS06 1532-SS12 SD0527 1532-AS07 1532-SS12 SD0528 1532-AS08 1532-SS12 SD0529 1532-AS09 1532-SS12 SD0530 1532-AS10 1532-SS12 SD0531 1532-AS11 1532-SS12 SD0532 1532-AS12 1532-SS12 SD0533 1532-AS13 1532-SS12 SD0534 1532-AS00 1532-SS13 SD0535 1532-AS01 1532-SS13 SD0536 1532-AS02 1532-SS13 SD0537 1532-AS03 1532-SS13 SD0538 1532-AS04 1532-SS13 SD0539 1532-AS05 1532-SS13 SD0540 1532-AS06 1532-SS13 SD0541 1532-AS07 1532-SS13 SD0542 1532-AS08 1532-SS13 SD0543 1532-AS09 1532-SS13 SD0544 1532-AS10 1532-SS13 SD0545 1532-AS11 1532-SS13 SD0546 1532-AS12 1532-SS13 SD0547 1532-AS13 1532-SS13 SD0548 1532-AS00 1532-SS14 SD0549 1532-AS01 1532-SS14 SD0550 1532-AS02 1532-SS14 SD0551 1532-AS03 1532-SS14 SD0552 1532-AS04 1532-SS14 SD0553 1532-AS05 1532-SS14 SD0554 1532-AS06 1532-SS14 SD0555 1532-AS07 1532-SS14 SD0556 1532-AS08 1532-SS14 SD0557 1532-AS09 1532-SS14 SD0558 1532-AS10 1532-SS14 SD0559 1532-AS11 1532-SS14 SD0560 1532-AS12 1532-SS14 SD0561 1532-AS13 1532-SS14 SD0562 1532-AS00 1532-SS15 SD0563 1532-AS01 1532-SS15 SD0564 1532-AS02 1532-SS15 SD0565 1532-AS03 1532-SS15 SD0566 1532-AS04 1532-SS15 SD0567 1532-AS05 1532-SS15 SD0568 1532-AS06 1532-SS15 SD0569 1532-AS07 1532-SS15 SD0570 1532-AS08 1532-SS15 SD0571 1532-AS09 1532-SS15 SD0572 1532-AS10 1532-SS15 SD0573 1532-AS11 1532-SS15 SD0574 1532-AS12 1532-SS15 SD0575 1532-AS13 1532-SS15 SD0576 1532-AS00 1532-SS16 SD0577 1532-AS01 1532-SS16 SD0578 1532-AS02 1532-SS16 SD0579 1532-AS03 1532-SS16 SD0580 1532-AS04 1532-SS16 SD0581 1532-AS05 1532-SS16 SD0582 1532-AS06 1532-SS16 SD0583 1532-AS07 1532-SS16 SD0584 1532-AS08 1532-SS16 SD0585 1532-AS09 1532-SS16 SD0586 1532-AS10 1532-SS16 SD0587 1532-AS11 1532-SS16 SD0588 1532-AS12 1532-SS16 SD0589 1532-AS13 1532-SS16 SD0590 1532-AS00 1532-SS17 SD0591 1532-AS01 1532-SS17 SD0592 1532-AS02 1532-SS17 SD0593 1532-AS03 1532-SS17 SD0594 1532-AS04 1532-SS17 SD0595 1532-AS05 1532-SS17 SD0596 1532-AS06 1532-SS17 SD0597 1532-AS07 1532-SS17 SD0598 1532-AS08 1532-SS17 SD0599 1532-AS09 1532-SS17 SD0600 1532-AS10 1532-SS17 SD0601 1532-AS11 1532-SS17 SD0602 1532-AS12 1532-SS17 SD0603 1532-AS13 1532-SS17 SD0604 1532-AS00 1532-SS18 SD0605 1532-AS01 1532-SS18 SD0606 1532-AS02 1532-SS18 SD0607 1532-AS03 1532-SS18 SD0608 1532-AS04 1532-SS18 SD0609 1532-AS05 1532-SS18 SD0610 1532-AS06 1532-SS18 SD0611 1532-AS07 1532-SS18 SD0612 1532-AS08 1532-SS18 SD0613 1532-AS09 1532-SS18 SD0614 1532-AS10 1532-SS18 SD0615 1532-AS11 1532-SS18 SD0616 1532-AS12 1532-SS18 SD0617 1532-AS13 1532-SS18 SD0618 1532-AS00 1532-SS19 SD0619 1532-AS01 1532-SS19 SD0620 1532-AS02 1532-SS19 SD0621 1532-AS03 1532-SS19 SD0622 1532-AS04 1532-SS19 SD0623 1532-AS05 1532-SS19 SD0624 1532-AS06 1532-SS19 SD0625 1532-AS07 1532-SS19 SD0626 1532-AS08 1532-SS19 SD0627 1532-AS09 1532-SS19 SD0628 1532-AS10 1532-SS19 SD0629 1532-AS11 1532-SS19 SD0630 1532-AS12 1532-SS19 SD0631 1532-AS13 1532-SS19 SD0632 1532-AS00 1532-SS20 SD0633 1532-AS01 1532-SS20 SD0634 1532-AS02 1532-SS20 SD0635 1532-AS03 1532-SS20 SD0636 1532-AS04 1532-SS20 SD0637 1532-AS05 1532-SS20 SD0638 1532-AS06 1532-SS20 SD0639 1532-AS07 1532-SS20 SD0640 1532-AS08 1532-SS20 SD0641 1532-AS09 1532-SS20 SD0642 1532-AS10 1532-SS20 SD0643 1532-AS11 1532-SS20 SD0644 1532-AS12 1532-SS20 SD0645 1532-AS13 1532-SS20 SD0646 1532-AS00 1532-SS21 SD0647 1532-AS01 1532-SS21 SD0648 1532-AS02 1532-SS21 SD0649 1532-AS03 1532-SS21 SD0650 1532-AS04 1532-SS21 SD0651 1532-AS05 1532-SS21 SD0652 1532-AS06 1532-SS21 SD0653 1532-AS07 1532-SS21 SD0654 1532-AS08 1532-SS21 SD0655 1532-AS09 1532-SS21 SD0656 1532-AS10 1532-SS21 SD0657 1532-AS11 1532-SS21 SD0658 1532-AS12 1532-SS21 SD0659 1532-AS13 1532-SS21 SD0660 1532-AS00 1532-SS22 SD0661 1532-AS01 1532-SS22 SD0662 1532-AS02 1532-SS22 SD0663 1532-AS03 1532-SS22 SD0664 1532-AS04 1532-SS22 SD0665 1532-AS05 1532-SS22 SD0666 1532-AS06 1532-SS22 SD0667 1532-AS07 1532-SS22 SD0668 1532-AS08 1532-SS22 SD0669 1532-AS09 1532-SS22 SD0670 1532-AS10 1532-SS22 SD0671 1532-AS11 1532-SS22 SD0672 1532-AS12 1532-SS22 SD0673 1532-AS13 1532-SS22 SD0674 1532-AS00 1532-SS23 SD0675 1532-AS01 1532-SS23 SD0676 1532-AS02 1532-SS23 SD0677 1532-AS03 1532-SS23 SD0678 1532-AS04 1532-SS23 SD0679 1532-AS05 1532-SS23 SD0680 1532-AS06 1532-SS23 SD0681 1532-AS07 1532-SS23 SD0682 1532-AS08 1532-SS23 SD0683 1532-AS09 1532-SS23 SD0684 1532-AS10 1532-SS23 SD0685 1532-AS11 1532-SS23 SD0686 1532-AS12 1532-SS23 SD0687 1532-AS13 1532-SS23 SD0688 1532-AS00 1532-SS24 SD0689 1532-AS01 1532-SS24 SD0690 1532-AS02 1532-SS24 SD0691 1532-AS03 1532-SS24 SD0692 1532-AS04 1532-SS24 SD0693 1532-AS05 1532-SS24 SD0694 1532-AS06 1532-SS24 SD0695 1532-AS07 1532-SS24 SD0696 1532-AS08 1532-SS24 SD0697 1532-AS09 1532-SS24 SD0698 1532-AS10 1532-SS24 SD0699 1532-AS11 1532-SS24 SD0700 1532-AS12 1532-SS24 SD0701 1532-AS13 1532-SS24 SD0702 1532-AS14 1532-SS00 SD0703 1532-AS15 1532-SS00 SD0704 1532-AS16 1532-SS00 SD0705 1532-AS17 1532-SS00 SD0706 1532-AS18 1532-SS00 SD0707 1532-AS19 1532-SS00 SD0708 1532-AS20 1532-SS00 SD0709 1532-AS21 1532-SS00 SD0710 1532-AS22 1532-SS00 SD0711 1532-AS23 1532-SS00 SD0712 1532-AS24 1532-SS00 SD0713 1532-AS25 1532-SS00 SD0714 1532-AS26 1532-SS00 SD0715 1532-AS27 1532-SS00

In some embodiments, an LPA RNAi agent comprises an antisense strand comprising the nucleotide sequence of SEQ ID NO:1242 (TCGUAUAACAAUAAGGGGC). In some embodiments, an LPA RNAi agent comprises an antisense strand comprising the nucleotide sequence of SEQ ID NO:1244 (UCGUAUAACAAUAAGGGG). In some embodiments, an LPA RNAi agent comprises an antisense strand comprising the nucleotide sequence of SEQ ID NO:1246 (UCGUAUAACAAUAAGGG). In some embodiments, an LPA RNAi agent comprises an antisense strand comprising the nucleotide sequence of SEQ ID NO:1248 (TGAGAAUGAGCCUCGAUAA). In some embodiments, an LPA RNAi agent comprises an antisense strand comprising the nucleotide sequence of SEQ ID NO:1250 (UGAGAAUGAGCCUCGAUA). In some embodiments, an LPA RNAi agent comprises an antisense strand comprising the nucleotide sequence of SEQ ID NO:1252 (UGAGAAUGAGCCUCGAU). In some embodiments, an LPA RNAi agent comprises an antisense strand comprising the nucleotide sequence of SEQ ID NO:1254 (UGUAUAACAAUAAGGGG). In some embodiments, an LPA RNAi agent comprises an antisense strand comprising the nucleotide sequence of SEQ ID NO:1280 (CGUAUAACAAUAAGGGGC). In some embodiments, an LPA RNAi agent comprises an antisense strand comprising the nucleotide sequence of SEQ ID NO:1281 (GAGAAUGAGCCUCGAUAA). In some embodiments, an LPA RNAi agent comprises an antisense strand comprising the nucleotide sequence of SEQ ID NO:1282 (UCGUAUAACAAUAAGGGGC). In some embodiments, an LPA RNAi agent comprises an antisense strand comprising the nucleotide sequence of SEQ ID NO:1283 (UGAGAAUGAGCCUCGAUAA). In some embodiments, one or more of the nucleotides is modified.

In some embodiments, an LPA RNAi agent comprises a sense strand comprising the nucleotide sequence of SEQ ID NO:1243 (GCCCCUUAUUGUUAUACGA). In some embodiments, an LPA RNAi agent comprises a sense strand comprising the nucleotide sequence of SEQ ID NO:1245 (CCCCUUAUUGUUAUACGA). In some embodiments, an LPA RNAi agent comprises a sense strand comprising the nucleotide sequence of SEQ ID NO:1247 (CCCUUAUUGUUAUACGA). In some embodiments, an LPA RNAi agent comprises a sense strand comprising the nucleotide sequence of SEQ ID NO:1249 (UUAUCGAGGCUCAUUCUCA). In some embodiments, an LPA RNAi agent comprises a sense strand comprising the nucleotide sequence of SEQ ID NO:1251 (UAUCGAGGCUCAUUCUCA). In some embodiments, an LPA RNAi agent comprises a sense strand comprising the nucleotide sequence of SEQ ID NO:1253 (AUCGAGGCUCAUUCUCA). In some embodiments, an LPA RNAi agent comprises a sense strand comprising the nucleotide sequence of SEQ ID NO:1255 (CCCCUUAUUGUUAUACA). In some embodiments, an LPA RNAi agent comprises a sense strand comprising the nucleotide sequence of SEQ ID NO:1284 (GCCCCUUAUUGUUAUACG). In some embodiments, an LPA RNAi agent comprises a sense strand comprising the nucleotide sequence of SEQ ID NO:1285 (UUAUCGAGGCUCAUUCUC). In some embodiments, one or more of the nucleotides is modified.

In some embodiments, an LPA RNAi agent comprises an antisense strand comprising the nucleotide sequence of SEQ ID NO:1242 and a sense strand comprising the nucleotide sequence of SEQ ID NO:1243. In some embodiments, an LPA RNAi agent comprises an antisense strand comprising the nucleotide sequence of SEQ ID NO:1244 and a sense strand comprising the nucleotide sequence of SEQ ID NO:1245. In some embodiments, an LPA RNAi agent comprises an antisense strand comprising the nucleotide sequence of SEQ ID NO:1246 and a sense strand comprising the nucleotide sequence of SEQ ID NO:1247. In some embodiments, an LPA RNAi agent comprises an antisense strand comprising the nucleotide sequence of SEQ ID NO:1248 and a sense strand comprising the nucleotide sequence of SEQ ID NO:1249. In some embodiments, an LPA RNAi agent comprises an antisense strand comprising the nucleotide sequence of SEQ ID NO:1250 and a sense strand comprising the nucleotide sequence of SEQ ID NO:1251. In some embodiments, an LPA RNAi agent comprises an antisense strand comprising the nucleotide sequence of SEQ ID NO:1252 and a sense strand comprising the nucleotide sequence of SEQ ID NO:1253. In some embodiments, an LPA RNAi agent comprises an antisense strand comprising the nucleotide sequence of SEQ ID NO:1254 and sense strand comprising the nucleotide sequence of SEQ ID NO:1255. In some embodiments, an LPA RNAi agent comprises an antisense strand comprising the nucleotide sequence of SEQ ID NO:1280 and a sense strand comprising the nucleotide sequence of SEQ ID NO:1284. In some embodiments, an LPA RNAi agent comprises an antisense strand comprising the nucleotide sequence of SEQ ID NO:1281 and a sense strand comprising the nucleotide sequence of SEQ ID NO: 1285. In some embodiments, an LPA RNAi agent comprises an antisense strand comprising the nucleotide sequence of SEQ ID NO:1282 and a sense strand comprising the nucleotide sequence of SEQ ID NO:1259. In some embodiments, an LPA RNAi agent comprises an antisense strand comprising the nucleotide sequence of SEQ ID NO:1283 and a sense strand comprising the nucleotide sequence of SEQ ID NO: 1249. In some embodiments, one or more of the nucleotides is modified.

In some embodiments, an LPA RNAi agent comprises an antisense strand comprising the nucleotide sequence of SEQ ID NO. 156, 164, or 188. In some embodiments, an LPA RNAi agent comprises a sense strand comprising the nucleotide sequence of SEQ ID NO. 310, 357, 384, or 376. In some embodiments, an LPA RNAi agent comprises an antisense strand and a sense strand comprising the nucleotide sequences of SEQ ID NOs:156/310, SEQ ID NOs:164/357, SEQ ID NOs:188/384, SEQ ID NOs:164/376, or SEQ ID NOs:164/384. In some embodiments, one or more of the nucleotides is modified.

In some embodiments, an LPA RNAi agent comprises an antisense strand comprising the nucleotide sequence of SEQ ID NO. 637, 709, 790, 787, or 788. In some embodiments, an LPA RNAi agent comprises a sense strand comprising the nucleotide sequence of SEQ ID NO:1132, 1135, 1189, 1191, or 1186. In some embodiments, an LPA RNAi agent comprises an antisense strand and a sense strand comprising the nucleotide sequences of SEQ ID NOs:637/1132, SEQ ID NOs:709/1135, SEQ ID NOs:790/1189, SEQ ID NOs:787/1191, or SEQ ID NOs:788/1186.

In some embodiments, an LPA RNAi agent comprises SEQ ID NO. 637, 709, 790, 787, or 788. In some embodiments, an LPA RNAi agent comprises SEQ ID NO:1132, 1135, 1189, 1191, or 1186. In some embodiments, an LPA RNAi agent comprises SEQ ID NOs:637/1132, SEQ ID NOs:709/1135, SEQ ID NOs:790/1189, SEQ ID NOs:787/1191, or SEQ ID NOs:788/1186.

In some embodiments, an LPA RNAi agent consists of SEQ ID NO. 637, 709, 790, 787, or 788. In some embodiments, an LPA RNAi agent consists of SEQ ID NO:1132, 1135, 1189, 1191, or 1186. In some embodiments, an LPA RNAi agent consists of SEQ ID NOs:637/1132, SEQ ID NOs:709/1135, SEQ ID NOs:790/1189, SEQ ID NOs:787/1191, or SEQ ID NOs:788/1186.

In some embodiments, an LPA RNAi agent comprises an antisense strand and a sense strand having the nucleotide sequences of any of the antisense strand/sense strand duplexes of Table 3A or 3B.

In some embodiments, an LPA RNAi agent comprises an antisense strand and a sense strand having the nucleotide sequences of any of the antisense strand/sense strand duplexes of Table 3A or 3B, and further comprises an asialoglycoprotein receptor ligand targeting group.

In some embodiments, an LPA RNAi agent comprises an antisense strand and a sense strand having the nucleotide sequences of any of the antisense strand/sense strand duplexes of Table 3A or 3B, and further comprises a targeting group selected from the group consisting of (C11PEG3NAG3), (C11-PEG5-NAG5), (C6-PEG4-NAG3), (NAG 3), (NAG4), (NAG5-1AA2), (NAG5-Palm), (NAG13), (NAG18), (NAG24), (NAG25), (NAG25)s, (NAG26), (NAG27), (NAG28), (NAG29), (NAG30), (NAG30)s, (NAG31), (NAG13), (NAG31s), (NAG32), (NAG33), (NAG34), (NAG35), (NAG36), and (NAG37).

In some embodiments, an LPA RNAi agent comprises an antisense strand and a sense strand having the modified nucleotide sequences of any of the antisense strand/sense strand duplexes of Table 3A or 3B.

In some embodiments, an LPA RNAi agent comprises an antisense strand and a sense strand having the modified nucleotide sequences of any of the antisense strand/sense strand duplexes of Table 3A or 3B, and further comprises an asialoglycoprotein receptor ligand targeting group.

In some embodiments, an LPA RNAi agent comprises an antisense strand and a sense strand having the modified nucleotide sequences of any of the antisense strand/sense strand duplexes of Table 3A or 3B, and further comprises a targeting group selected from the group consisting of (C11-PEG5-NAG5), (C11-PEG5-NAG5), (C6-PEG4-NAG3), (NAG 3), (NAG4), (NAG3-AA2), (NAG5-Palm), (NAG13), (NAG18), (NAG24), (NAG25), (NAG25)s, (NAG26), (NAG27), (NAG28), (NAG29), (NAG30), (NAG30)s, (NAG31), (NAG13), (NAG31s), (NAG32), (NAG33), (NAG34), (NAG35), (NAG36), and (NAG37).

In some embodiments, an LPA RNAi agent comprises any of the duplexes of Table 3A or 3B.

In some embodiments, an LPA RNAi agent consists of any of the duplexes of Table 3A or 3B.

In some embodiments, an LPA RNAi agent comprises an antisense strand and a sense strand having the nucleotide sequences AD03460, AD03536, AD03581, AD03583, AD3847, or AD04110.

In some embodiments, an LPA RNAi agent comprises an antisense strand and a sense strand having the nucleotide sequences AD03460, AD03536, AD03581, AD03583, AD3847, or AD04110, and further comprises an asialoglycoprotein receptor ligand targeting group.

In some embodiments, an LPA RNAi agent comprises an antisense strand and a sense strand having the nucleotide sequences AD03460, AD03536, AD03581, AD03583, AD3847, or AD04110, and further comprises a targeting group selected from the group consisting of (C11-PEG5-NAG5), (C11-PEG5-NAG5), (C6-PEG4-NAG3), (NAG 3), (NAG4), (NAG3-AA2), (NAG5-Palm), (NAG13), (NAG18), (NAG24), (NAG25), (NAG25)s, (NAG26), (NAG27), (NAG28), (NAG29), (NAG30), (NAG30)s, (NAG31), (NAG13), (NAG31s), (NAG32), (NAG33), (NAG34), (NAG35), (NAG36), and (NAG37).

In some embodiments, an LPA RNAi agent comprises an antisense strand and a sense strand having the modified nucleotide sequences AD03460, AD03536, AD03581, AD03583, AD3847, or AD04110.

In some embodiments, an LPA RNAi agent comprises an antisense strand and a sense strand having the modified nucleotide sequences AD03460, AD03536, AD03581, AD03583, AD3847, or AD04110, and further comprises an asialoglycoprotein receptor ligand targeting group.

In some embodiments, an LPA RNAi agent comprises an antisense strand and a sense strand having the modified nucleotide sequences AD03460, AD03536, AD03581, AD03583, AD3847, or AD04110, and further comprises a targeting group selected from the group consisting of (C11-PEG5-NAG5), (C11-PEG5-NAG5), (C6-PEG4-NAG3), (NAG5), (NAG4), (NAG3-AA2), (NAG5-Palm), (NAG13), (NAG18), (NAG24), (NAG25), (NAG25)s, (NAG26), (NAG27), (NAG28), (NAG29), (NAG30), (NAG30)s, (NAG31), (NAG13), (NAG31s), (NAG32), (NAG33), (NAG34), (NAG35), (NAG36), and (NAG37).

In some embodiments, an LPA RNAi agent comprises AD03460, AD03536, AD03581, AD03583, AD3847, or AD04110.

In some embodiments, an LPA RNAi agent consists of AD03460, AD03536, AD03581, AD03583, AD3847, or AD04110.

Non-Nucleotide Group

In some embodiments, an LPA RNAi agent contains or is conjugated to one or more non-nucleotide groups including, but not limited to a targeting group, linking group, delivery polymer, or a delivery vehicle. The non-nucleotide group can enhance targeting, delivery or attachment of the RNAi agent. Examples of targeting groups and linking groups are provided in Table 4. The non-nucleotide group can be covalently linked to the 3′ and/or 5′ end of either the sense strand and/or the antisense strand. In some embodiments, an LPA RNAi agent contains a non-nucleotide group linked to the 3′ and/or 5′ end of the sense strand. In some embodiments a non-nucleotide group is linked to the 5′ end of an LPA RNAi agent sense strand. A non-nucleotide group may linked directly or indirectly to the RNAi agent via a linker/linking group. In some embodiments a non-nucleotide group is linked to the RNAi agent via a labile, cleavable, or reversible bond or linker.

In some embodiments, a non-nucleotide group enhances the pharmacokinetic or biodistribution properties of an RNAi agent or conjugate to which it is attached to improve cell- or tissue-specific distribution and cell-specific uptake of the conjugate. In some embodiments, a non-nucleotide group enhances endocytosis of the RNAi agent.

Targeting Group

A targeting group can be monovalent, divalent, trivalent, tetravalent, or have higher valency. Representative targeting groups include, without limitation, compounds with affinity to cell surface molecule, cell receptor ligands, hapten, antibodies, monoclonal antibodies, antibody fragments, and antibody mimics with affinity to cell surface molecules. In some embodiments, a targeting group is linked to an RNAi agent using a linker, such as a PEG linker or one, two, or three abasic and/or ribitol groups. In some embodiments, a targeting group comprises a galactose cluster.

The LPA RNAi agents described herein may be synthesized having a reactive group, such as an amine group, at the 5′-terminus. The reactive group may be used to subsequently attach a targeting moiety using methods typical in the art.

In some embodiments, a targeting group comprises an asialoglycoprotein receptor ligand. In some embodiments, an asialoglycoprotein receptor ligand includes or consists of one or more galactose derivatives or galactose clusters. As used herein, the term galactose derivative includes both galactose and derivatives of galactose having affinity for the asialoglycoprotein receptor that is equal to or greater than that of galactose. Galactose derivatives include, but are not limited to: galactose, galactosamine, N-formylgalactosamine, N-acetyl-galactosamine, N-propionyl-galactosamine, N-n-butanoyl-galactosamine, and N-iso-butanoylgalactos-amine (see for example: Iobst, S. T. and Drickamer, K. J.B.C. 1996, 271, 6686). Galactose derivatives and galactose clusters that are useful for in vivo targeting of oligonucleotides and other molecules to the liver are known in the art (see, for example, Baenziger and Fiete, 1980, Cell, 22, 611-620; Connolly et al., 1982, J. Biol. Chem., 257, 939-945). Galactose derivatives have been used to target molecules to hepatocytes in vivo through their binding to the asialoglycoprotein receptor (ASGPr) expressed on the surface of hepatocytes. Binding of ASGPr ligands to the ASGPr(s) facilitates cell-specific targeting to hepatocytes and endocytosis of the molecule into hepatocytes. The galactose cluster may be attached to the 3′ or 5′ end of the RNAi polynucleotide using methods known in the art.

As used herein, a galactose cluster comprises a molecule having two to four terminal galactose derivatives. A terminal galactose derivative is attached to a molecule through its C-1 carbon. In some embodiments, the galactose cluster is a galactose derivative trimer, tri-antennary galactose derivative, or tri-valent galactose derivative. In some embodiments, the galactose cluster is comprises N-acetylgalactosamines (GalNAc). In some embodiments, the galactose cluster comprises a tri-valent N-acetyl-galactosamine. In some embodiments, the galactose cluster is a galactose derivative tetramer, tetra-antennary galactose derivative, or tetra-valent galactose derivative. In some embodiments, the galactose cluster comprises a tetra-valent N-acetyl-galactosamine

As used herein, a galactose trimer contains three galactose derivatives, each linked to a central branch point. As used herein, a galactose derivative tetramer contains four galactose derivatives, each linked to a central branch point. The galactose derivatives can be attached to the central branch point through the C-1 carbons of the saccharides. In some embodiments, the galactose derivatives are linked to the branch point via linkers or spacers. In some embodiments, the linker or spacer is a flexible hydrophilic spacer, such as a PEG group (see, for example, U.S. Pat. No. 5,885,968; Biessen et al. J. Med. Chem. 1995 Vol. 39 p. 1538-1546). In some embodiments, the PEG spacer is a PEG3 spacer. The branch point can be any small molecule which permits attachment of the three galactose derivatives and further permits attachment of the branch point to the RNAi agent. An example of branch point group is a di-lysine or di-glutamate. Attachment of the branch point to the RNAi agent can occur through a linker or spacer. In some embodiments, the linker or spacer comprises a flexible hydrophilic spacer, such as, but not limited to: a PEG spacer. In some embodiments, a PEG spacer is a PEG₃ spacer (three ethylene units). In other embodiments, the PEG spacer has 1 to 20 ethylene units (PEG₁ to PEG₂₀). In some embodiments, a galactose derivative comprises an N-acetylgalactosamine (GalNAc or NAG). In some embodiments, the galactose cluster is comprised of a galactose derivative tetramer, which can be, for example, an N-acetyl-galactosamine tetramer.

In some embodiments, pharmaceutical compositions for delivering an LPA RNAi agent to a liver cell in vivo are described. Such pharmaceutical compositions can include, for example, an LPA RNAi agent conjugated to a galactose cluster. In some embodiments, the galactose cluster is comprised of a galactose derivative trimer, which can be, for example, an N-acetyl-galactosamine trimer, or galactose derivative tetramer, which can be, for example, an N-acetyl-galactosamine tetramer.

Targeting groups include, but are not limited to, (Chol-TEG), (TEG-Chol), (C11-PEG5-NAG5), (C_(m)-PEG_(n)-NAG3), (C_(x)-PEG_(z)-NAG3), (NAG 3), (NAG4), (NAG3-AA2), (NAG3-Palm), (NAG13), (NAG18), (NAG24), (NAG25), (NAG25)s, (NAG26), (NAG27), (NAG28), (NAG29), (NAG30), (NAG30)s, (NAG31), (NAG13), (NAG31s), (NAG32), (NAG33), (NAG34), (NAG35), (NAG36), and (NAG37).

Linking Group

In some embodiments, a linking group is conjugated to the RNAi agent. The linking group facilitates covalent linkage of the agent to a targeting group or delivery polymer or delivery vehicle. The linking group can be linked to the 3′ or the 5′ end of the RNAi agent sense strand or antisense strand. In some embodiments, the linking group is linked to the RNAi agent sense strand. In some embodiments, the linking group is conjugated to the 5′ or 3′ end of an RNAi agent sense strand. In some embodiments a linking group is conjugated to the 5′ end of an RNAi agent sense strand. Examples of linking groups, include, but are not limited to: Alk-SMPT-C6, Alk-SS-C6, DBCO-TEG, Me-Alk-SS-C6, and C6-SS-Alk-Me, reactive groups such a primary amines and alkynes, alkyl groups, abasic ribose, ribitol, and/or PEG groups.

A linker or linking group is a connection between two atoms that links one chemical group (such as an RNAi agent) or segment of interest to another chemical group (such as a targeting group or delivery polymer) or segment of interest via one or more covalent bonds. A labile linkage contains a labile bond. A linkage may optionally include a spacer that increases the distance between the two joined atoms. A spacer may further add flexibility and/or length to the linkage. Spacers may include, but are not be limited to, alkyl groups, alkenyl groups, alkynyl groups, aryl groups, aralkyl groups, aralkenyl groups, and aralkynyl groups; each of which can contain one or more heteroatoms, heterocycles, amino acids, nucleotides, and saccharides. Spacer groups are well known in the art and the preceding list is not meant to limit the scope of the description.

Linking groups include, but are not limited to, Alkyl, PEG, (C6-PEG_(n)-Alk), (C_(n)-SMPT-Alk), and (C_(n)-SS-Alk-Me).

Any of the LPA RNAi agents listed in Tables 2A and 2B which contains a 3′ or 5′ targeting group or linking group, may alternatively contain no 3′ or 5′ targeting group or linking group, or may contain a different 3′ or 5′ targeting group or linking group including, but not limited to, those depicted in Table 4. Any of the LPA RNAi agent nucleotide sequences listed in Tables 1, 2A and 2B, whether modified or unmodified, may contain 3′ or 5′ targeting group or linking group, including, but not limited to, those depicted in Table 4. Any of the LPA RNAi agent duplexes listed in Tables 3A and 3B, whether modified or unmodified, may further comprise a targeting group or linking group, including, but not limited to, those depicted in Table 4, and the targeting group or linking group may be attached to the 3′ or 5′ terminus of either the sense strand or the antisense strand of the LPA RNAi agent duplex.

TABLE 4 Structures representing various modified nucleotides, targeting groups, and linking groups.

In each of the above structures, NAG comprises an N-Acetyl-Galactosamine or another ASGPR ligand. Each (NAGx) may be attached to an LPA RNAi agent via a phosphate group (as in (NAG25), (NAG30), and (NAG31)), or a phosphorothioate group, (as is (NAG25)s, (NAG30)s, and (NAG31)s), or another linking group. Alternatively, other linking groups known in the art may be used.

Delivery Vehicles

In some embodiments, a delivery vehicle may be used to deliver an RNAi agent to a cell or tissue. A delivery vehicle is a compound that improves delivery of the RNAi agent to a cell or tissue. A delivery vehicle can include, or consist of, but is not limited to: a polymer, such as an amphipathic polymer, a membrane active polymer, a peptide, a melittin peptide, a melittin-like peptide (MLP), a lipid, a reversibly modified polymer or peptide, or a reversibly modified membrane active polyamine

In some embodiments, the RNAi agents can be combined with lipids, nanoparticles, polymers, liposomes, micelles, DPCs or other delivery systems available in the art. The RNAi agents can also be chemically conjugated to targeting groups, lipids (including, but not limited to cholesterol and cholesteryl derivatives), nanoparticles, polymers, liposomes, micelles, DPCs (see, for example WO 2000/053722, WO 2008/0022309, WO 2011/104169, and WO 2012/083185, WO 2013/032829, WO 2013/158141, each of which is incorporated herein by reference), or other delivery systems available in the art.

Pharmaceutical Compositions

Described herein are methods for delivering LPA RNAi agents to liver cells in a mammal in vivo. In some embodiments, a delivery vehicle may be used. A delivery vehicle is a compound which improves delivery of the RNAi agent to the cell. A delivery vehicle can be, but is not limited to: a polymer, such as an amphipathic polymer, membrane active polymer, a peptide, such as a melittin or melittin-like peptide, a reversibly modified polymer or peptide, or a lipid. In some embodiments, an LPA RNAi agent is linked to a targeting ligand that comprises an asialoglycoprotein ligand. In some embodiments, an LPA RNAi agent is linked to a targeting ligand that comprises or consists of a galactose cluster.

An LPA RNAi agent can be used to inhibit expression of LPA in a cell, group of cells, or a tissue, e.g., in a subject. In some embodiments, an LPA RNAi agent is used to formulate a composition, i.e. a pharmaceutical composition or medicament, for administering to a subject. As used herein, a pharmaceutical composition or medicament comprises a pharmacologically effective amount of at least one of the described LPA RNAi agents and one or more pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients (excipients) are substances other than the Active Pharmaceutical ingredient (API, therapeutic product, e.g., LPA RNAi agent) that have been appropriately evaluated for safety and are intentionally included in the drug delivery system. Excipients do not exert or are not intended to exert a therapeutic effect at the intended dosage. Excipients may act to a) aid in processing of the drug delivery system during manufacture, b) protect, support or enhance stability, bioavailability or patient acceptability of the API, c) assist in product identification, and/or d) enhance any other attribute of the overall safety, effectiveness, of delivery of the API during storage or use. A pharmaceutically acceptable excipient may or may not be an inert substance.

Excipients include, but are not limited to: absorption enhancers, anti-adherents, anti-foaming agents, anti-oxidants, binders, binders, buffering agents, carriers, coating agents, colors, delivery enhancers, delivery polymers, dextran, dextrose, diluents, disintegrants, emulsifiers, extenders, fillers, flavors, glidants, humectants, lubricants, oils, polymers, preservatives, saline, salts, solvents, sugars, suspending agents, sustained release matrices, sweeteners, thickening agents, tonicity agents, vehicles, water-repelling agents, and wetting agents.

A pharmaceutical composition can contain other additional components commonly found in pharmaceutical compositions. Such additional components include, but are not limited to: anti-pruritics, astringents, local anesthetics, or anti-inflammatory agents (e.g., antihistamine, diphenhydramine, etc.). It is also envisioned that cells, tissues or isolated organs that express or comprise the herein defined RNAi agents may be used as “pharmaceutical compositions”. As used herein, “pharmacologically effective amount,” “therapeutically effective amount,” or simply “effective amount” refers to that amount of an RNAi agent to produce the intended pharmacological, therapeutic or preventive result.

In some embodiments, a described LPA RNAi agent is combined one or more additional therapeutics or treatments including, but not limited to: a second LPA RNAi agent or other RNAi agent, a small molecule drug, an antibody, an antibody fragment, and/or a vaccine. Examples of additional therapeutics include, but are not limited to, HMg Co-A reductase inhibitors (statins), ezetimibe, PCSK-9 inhibitors, CTEP inhibitors, therapies targeting ANGPTL3, therapies targeting APOC3, and niacin.

The described RNAi agents and pharmaceutical compositions comprising LPA RNAi agents disclosed herein may be packaged or included in a kit, container, pack, or dispenser. The LPA RNAi agents and pharmaceutical compositions comprising said LPA RNAi agents may be packaged in pre-filled syringes or vials.

In some embodiments, pharmaceutical compositions comprising at least one of the described LPA RNAi agents are contemplated. These pharmaceutical compositions are useful in the inhibition of the expression of the LPA gene in a cell, a tissue, or an organism. In some embodiments, the described pharmaceutical compositions are used to treat a subject having a disease, condition, or disorder that would benefit from reduction or inhibition in LPA expression. In some embodiments, the described pharmaceutical compositions are used to treat a subject at risk of developing a disease, condition, or disorder that would benefit from reduction or inhibition in LPA expression. Diseases, conditions, or disorders that would benefit from reduction or inhibition in LPA expression include, but are not limited to: Berger's disease, peripheral artery disease, coronary artery disease, metabolic syndrome, acute coronary syndrome, aortic valve stenosis, aortic valve regurgitation, aortic dissection, retinal artery occlusion, cerebrovascular disease, mesenteric ischemia, superior mesenteric artery occlusion, renal artery stenosis, stable/unstable angina, acute coronary syndrome, heterozygous or homozygous familial hypercholesterolemia, hyperapobetalipoproteinemia, cerebrovascular atherosclerosis, cerebrovascular disease, and venous thrombosis. In some embodiments, the subject is a mammal, including, but not limited to, a human patient.

Cells, tissues, and non-human organisms that include at least one of the LPA RNAi agents described herein is contemplated. The cell, tissue, or non-human organism is made by delivering the RNAi agent to the cell, tissue, or non-human organism by any means available in the art. In some embodiments, the cell is a mammalian cell, including, but not limited to, a human cell. The cell, tissue, or non-human organisms are useful for research or as research tools (e.g., drug testing or diagnoses).

Method of Treatment

In some embodiments, the LPA RNAi agents described herein are used to treat a subject having a disease, condition, or disorder or at risk of having a disease, condition, or disorder that would benefit from reduction or inhibition in LPA expression. Treatment of a subject that would benefit from a reduction and/or inhibition of LPA gene expression includes therapeutic and/or prophylactic treatment. Examples of diseases, conditions, or disorders, include, but not limited to: Berger's disease, peripheral artery disease, coronary artery disease, metabolic syndrome, acute coronary syndrome, aortic valve stenosis, aortic valve regurgitation, aortic dissection, retinal artery occlusion, cerebrovascular disease, mesenteric ischemia, superior mesenteric artery occlusion, renal artery stenosis, stable/unstable angina, acute coronary syndrome, heterozygous or homozygous familial hypercholesterolemia, hyperapobetalipoproteinemia, cerebrovascular atherosclerosis, cerebrovascular disease, and venous thrombosis. In some embodiments, the method comprises administering a composition, such as a pharmaceutical composition, comprising an LPA RNAi agent described herein to a mammal to be treated.

In some embodiments, a therapeutically effective amount of one or more of the described LPA RNAi agents is administered to a subject, thereby inhibiting expression of LPA in the subject (e.g., an amount effective to inhibit expression of LPA in the subject). In some embodiments, one or more of the LPA RNAi agents described herein are used to treat a subject having a disease or disorder that would benefit from reduction or inhibition in LPA expression. In some embodiments, the described LPA RNAi agents are used to treat or prevent at least one symptom in a subject having a disease or disorder that would benefit from reduction or inhibition in LPA expression. The subject is administered a therapeutically effective amount of any one or more of the described RNAi agents thereby treating the symptom. In some embodiments, the subject is administered a prophylactically effective amount of any one or more of the described RNAi agents thereby preventing the at least one symptom.

In some embodiments, an LPA RNAi agent is used to treat or manage a clinical presentation wherein a subject in need of such treatment, prevention, or management is administered a therapeutically or prophylactically effective amount of one or more of the LPA RNAi agents or LPA RNAi agent-containing compositions described herein. In some embodiments, the method comprises administering a composition comprising an LPA RNAi agent described herein to a mammal to be treated.

In some embodiments, the methods further comprise the step of administering a second therapeutic or treatment. In some embodiments, the second therapeutic is another LPA RNAi agent (e.g., a LPA RNAi agent which targets a different sequence within the LPA target). In other embodiments, the second therapeutic can be selected from the group comprising: small molecule drug, antibody, antibody fragment, and vaccine.

The route of administration is the path by which an RNAi agent is brought into contact with the body. In general, methods of administering drugs and nucleic acids for treatment of a subject are well known in the art and can be applied to administration of the compositions described herein. The compounds described herein can be administered via any suitable route in a preparation appropriately tailored to the particular route. Thus, the compounds described herein can be administered by injection, for example, intravenously, intramuscularly, intracutaneously, subcutaneously, or intraperitoneally.

In some embodiments, the LPA RNAi agents or compositions described herein can be delivered to a cell, group of cells, tissue, or subject using oligonucleotide delivery technologies known in the art. In general, any suitable method recognized in the art for delivering a nucleic acid molecule (in vitro or in vivo) can be adapted for use with an LPA RNAi agent described herein. For example, delivery can be by local administration, (e.g., direct injection, implantation, or topical administering), systemic administration, or subcutaneous, intravenous, oral, intraperitoneal, or parenteral routes, including intracranial (e.g., intraventricular, intraparenchymal and intrathecal), intramuscular, transdermal, airway (aerosol), nasal, rectal, or topical (including buccal and sublingual) administration, In certain embodiments, the compositions are administered by subcutaneous or intravenous infusion or injection.

In some embodiments, the RNAi agents can be combined with lipids, nanoparticles, polymers, liposomes, micelles, DPCs or other delivery systems available in the art. The RNAi agents can also be chemically conjugated to targeting groups, lipids (including, but not limited to cholesterol and cholesteryl derivatives), nanoparticles, polymers, liposomes, micelles, DPCs (se e.g., WO 2000/053722, WO 2008/0022309, WO 2011/104169, and WO 2012/083185, each of which is incorporated herein by reference), or other delivery systems available in the art. An LPA RNAi agent can be conjugated to a delivery polymer. In some embodiments, the delivery polymer is a reversibly masked/modified amphipathic membrane active polyamine

Inhibition of Expression

As used herein, the terms “silence,” “reduce,” “inhibit,” “down-regulate,” or “knockdown gene expression,” when referring to an LPA gene, mean that the expression of the gene, as measured by the level of RNA transcribed from the gene or the level of polypeptide, protein, or protein subunit translated from the mRNA in a cell, group of cells, or tissue, in which the LPA gene is transcribed, is reduced when the cell, group of cells, or tissue, is treated with the described LPA RNAi agents as compared to a second cell, group of cells, or tissue that has or has not been so treated or compared to the same cell, group of cells, or tissue, prior to administration of the LPA RNAi agent.

In some embodiments, the gene expression level and/or mRNA level of LPA in a subject to whom a described LPA RNAi agent is administered is reduced by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 98% relative to the subject prior to being administered the LPA RNAi agent or to a subject not receiving the LPA RNAi agent. The gene expression level and/or mRNA level in the subject may be reduced in a cell, group of cells, and/or tissue of the subject. In some embodiments, the protein level of LPA in a subject to whom a described LPA RNAi agent has been administered is reduced by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 98% relative to the subject prior to being administered the LPA RNAi agent or to a subject not receiving the LPA RNAi agent. The protein level in the subject may be reduced in a cell, group of cells, tissue, blood, and/or other fluid of the subject. A reduction in gene expression, mRNA, or protein levels can be assessed by any methods known in the art. Reduction or decrease in LPA mRNA level and/or protein level are collectively referred to herein as a reduction or decrease in LPA or inhibiting or reducing the expression of LPA.

Introducing into a cell, when referring to an RNAi agent, means functionally delivering the RNAi agent into the cell. By functional delivery, it is meant that the RNAi agent is delivered to the cell and has the expected biological activity, (e.g., sequence-specific inhibition of gene expression).

Cells and Tissues and Non-Human Organisms

Cells, tissues, and non-human organisms that include at least one of the LPA RNAi agents described herein is contemplated. The cell, tissue, or non-human organism is made by delivering the RNAi agent to the cell, tissue, or non-human organism.

The above provided embodiments and items are now illustrated with the following, non-limiting examples.

EXAMPLES Example 1. RNAi Agent Synthesis

A) Synthesis. LPA RNAi agents were synthesized according to phosphoramidite technology on solid phase used in oligonucleotide synthesis. Depending on the scale either a MerMade96E (Bioautomation) or a MerMadel2 (Bioautomation) was used. Syntheses were performed on a solid support made of controlled pore glass (CPG, 500 Å or 600 Å, obtained from Prime Synthesis, Aston, Pa., USA). All DNA, 2′-modified RNA, and UNA phosphoramidites were purchased from Thermo Fisher Scientific (Milwaukee, Wis., USA). Specifically, the following 2′-O-Methyl phosphoramidites were used: (5′-O-dimethoxytrityl-N⁶-(benzoyl)-2′-O-methyl-adenosine-3′-O-(2-cyanoethyl-N,N-diisopropy-lamino) phosphoramidite, 5′-O-dimethoxy-trityl-N⁴-(acetyl)-2′-O-methyl-cytidine-3′-O-(2-cyanoethyl-N,N-diisopropyl-amino) phosphoramidite, (5′-O-dimethoxytrityl-N²-(isobutyryl)-2′-O-methyl-guanosine-3′-O-(2-cyano-ethyl-N,N-diisopropylamino)phosphoramidite, and 5′-O-dimethoxy-trityl-2′-O-methyl-uridine-3′-O-(2-cyanoethyl-N,N-diisopropylamino)phosphoramidite. The 2′-Deoxy-2′-fluoro-phosphor-amidites carried the same protecting groups as the 2′-O-methyl RNA amidites. The following UNA phosphoramidites were used: 5′-(4,4′-Dimethoxytrityl)-N-benzoyl-2′,3′-seco-adenosine, 2′-benzoyl-3′-[(2-cyanoethyl)-(N,N-diisopropyl)]-phosphor-amidite, 5′-(4,4′-Dimethoxytrityl)-N-acetyl-2,3′-seco-cytosine, 2′-benzoyl-3′-[(2-cyanoethyl)-(N,N-diiso-propyl)]-phosphoramidite, 5′-(4,4′-Dimethoxytrityl)-N-isobutyryl-2′,3′-seco-guanosine, 2′-benzoyl-3′-[(2-cyanoethyl)-(N,N-diisopropyl)l-phosphoramidite, and 5′-(4,4′-Dimethoxy-trityl)-2′,3′-seco-uridine, 2′-benzoyl-3′-[(2-cyanoethyl)-(N,N-diiso-propyl)]-phosphoramidite. All amidites were dissolved in anhydrous acetonitrile (50 mM) and molecular sieves (3A) were added. In order to introduce the TEG-Cholesterol at the 5′-end of the oligomers, the 1-Dimethoxytrityloxy-3-O-(N-cholesteryl-3-aminopropyl)-triethyleneglycol-glyceryl-2-O-(2-cyanoethyl)-(N,N-diisopropyl)-phosphoramidite from Glen Research (Sterling, Va., USA) was employed. The 5′-modifications were introduced without any modification of the synthesis cycle. 5-Benzylthio-1H-tetrazole (BTT, 250 mM in acetonitrile) was used as activator solution. Coupling times were 10 mM (RNA), 180 sec (Cholesterol), 90 sec (2′OMe and UNA), and 60 sec (2′F and DNA). In order to introduce phosphorothioate linkages, a 100 mM solution of 3-phenyl 1,2,4-dithiazoline-5-one (POS, obtained from PolyOrg, Inc., Leominster, Mass., USA) in anhydrous Acetonitrile was employed. See Tables 1, 2A, and 2B for specific sequences.

B. Cleavage and Deprotection of Support Bound Oligomer.

After finalization of the solid phase synthesis, the dried solid support was treated with a 1:1 volume solution of 40 wt. % methylamine in water and 28% ammonium hydroxide solution (Aldrich) for two hours at 30° C. The solution was evaporated and the solid residue was reconstituted in water (see below).

C. Purification.

Crude Cholesterol containing oligomers were purified by reverse phase HPLC using a Waters XBridge BEH300 C4 5u Prep column and a Shimadzu LC-8 system. Buffer A was 100 mM TEAA, pH 7.5 and contained 5% Acetonitrile and buffer B was 100 mM TEAA and contained 95% Acetonitrile. UV traces at 260 nm were recorded. Appropriate fractions were then run on size exclusion HPLC using a GE Healthcare XK 16/40 column packed with Sephadex G-25 medium with a running buffer of 100 mM ammonium bicarbonate, pH 6.7 and 20% Acetonitrile. Other crude oligomers were purified by anionic exchange HPLC using a TKSgel SuperQ-5PW 13u column and Shimadzu LC-8 system. Buffer A was 20 mM Tris, 5 mM EDTA, pH 9.0 and contained 20% Acetonitrile and buffer B was the same as buffer A with the addition of 1.5 M sodium chloride. UV traces at 260 nm were recorded. Appropriate fractions were pooled then run on size exclusion HPLC as described for cholesterol containing oligomers.

D. Annealing.

Complementary strands were mixed by combining equimolar solutions (sense and antisense) in 0.2×PBS (Phosphate-Buffered Saline, lx, Corning, Cellgro) to form the RNAi agents. This solution was placed into a thermomixer at 70° C., heated to 95° C., held at 95° C. for 5 mM, and cooled to room temperature slowly. Some RNAi agents were lyophilized and stored at −15 to −25° C. Duplex concentration was determined by measuring the solution absorbance on a UV-Vis spectrometer in 0.2×PBS. The solution absorbance at 260 nm was then multiplied by a conversion factor and the dilution factor to determine the duplex concentration. Unless otherwise stated, all conversion factor was 0.037 mg/(mL·cm). For some experiments, a conversion factor was calculated from an experimentally determined extinction coefficient.

Example 2. Primary In Vitro Analysis of LPA RNAi Agents

Candidate sequences identified as human and non-human primate cross-reactive by in silico analysis were screened. 108 in silico-identified potential LPA RNAi agents were synthesized and screened for efficacy in vitro in three groups. For screening purposes, the human LPA cDNA sequence (accession # NM_005577.1) was sub-cloned from a commercially available mammalian expression vector (Origene, Rockville, Md.) into a commercially-available, reporter-based screening plasmid, psiCHECK2 (Promega, Madison, Wis.) which generated a Renilla luciferase/LPA fusion mRNA. For LPA RNAi agent efficacy in the human background, Hep3B cells, a human hepatocellular carcinoma line, were plated at −10,000 cells per well in 96-well format. Each of the 108 LPA RNAi agents was co-transfected at two or three concentrations (1 nM and 0.1 nM, or 0.02, 0.2 and 2 nM) with 50-100 ng LPA-psiCHECK2 plasmid DNA per well and 0.2 μL LipoFectamine 2000 per well. Gene knockdown was determined by measuring Renilla luciferase levels normalized to the levels of constitutively-expressed firefly luciferase, also present on the psiCHECK2 plasmid, using the Dual Luciferase Reporter Assay (Promega, Madison, Wis.) (Tables 5A and 5B).

TABLE 5A In vitro analyses of LPA RNAi agents, inhibition of LPA expression. Relative R_(luc)-LPA expression Duplex 1 nM 0. 1 nM ID# Average SD Average SD AD00571 1.012 0.146 1.107 0.174 AD00572 0.776 0.062 1.075 0.089 AD00573 0.708 0.054 0.708 0.134 AD00574 0.441 0.028 0.525 0.056 AD00575 0.242 0.038 0.365 0.035 AD00576 0.166 0.047 0.341 0.073 AD00577 0.702 0.115 0.934 0.036 AD00578 0.272 0.008 0.599 0.200 AD00579 0.290 0.031 0.447 0.066 AD00580 0.825 0.145 0.991 0.123 AD00581 0.654 0.095 0.986 0.127 AD00582 0.610 0.178 0.791 0.244 AD00583 0.824 0.208 0.845 0.240 AD00584 0.800 0.150 0.683 0.077 AD00585 0.387 0.059 0.488 0.151 AD00586 0.754 0.116 0.927 0.103 AD00587 0.921 0.074 0.923 0.052 AD00588 0.763 0.203 0.954 0.169 AD00589 0.838 0.115 1.026 0.216 AD00590 0.959 0.091 0.991 0.285 AD00591 0.970 0.172 0.984 0.244 AD00592 0.600 0.060 0.886 0.069 AD00593 0.555 0.097 0.883 0.130 AD00594 0.645 0.056 0.567 0.008 AD00595 0.812 0.132 1.076 0.285 AD00596 0.658 0.116 0.787 0.153 AD00597 0.999 0.120 1.083 0.143 AD00598 0.501 0.067 0.631 0.036 AD00599 0.890 0.098 0.871 0.143 AD00600 0.393 0.018 0.729 0.172 AD00601 0.896 0.180 1.142 0.140 AD00602 0.653 0.134 0.955 0.062 AD00603 0.730 0.118 0.799 0.187 AD00604 0.892 0.058 0.956 0.107 AD00605 1.006 0.193 1.006 0.146 AD00606 0.509 0.039 0.570 0.054 AD00607 0.816 0.091 0.906 0.068 AD00608 0.883 0.111 1.158 0.054 AD00609 0.515 0.079 0.691 0.137 AD00610 0.628 0.057 0.748 0.090 AD00611 1.320 0.066 1.116 0.046 AD00612 1.103 0.193 1.100 0.052 AD00613 0.910 0.094 0.878 0.040 AD00614 1.101 0.111 1.097 0.043 AD00615 1.051 0.140 0.898 0.161 AD00616 0.898 0.101 1.029 0.042 AD00617 0.715 0.023 0.802 0.150 AD00618 0.434 0.073 0.441 0.199 AD00619 0.758 0.003 0.820 0.165 AD00620 0.984 0.124 0.926 0.080 AD00621 0.308 0.033 0.267 0.044 AD00622 0.493 0.072 0.790 0.009 AD00623 0.641 0.081 0.599 0.014 AD00624 0.795 0.019 0.985 0.123 AD00625 0.768 0.121 0.944 0.117 AD00626 0.981 0.081 1.036 0.036 AD00627 0.943 0.163 0.936 0.038 AD00628 0.765 0.069 0.995 0.090 AD00629 1.001 0.184 1.199 0.064 AD00630 0.963 0.149 1.154 0.141 AD00631 0.979 0.084 1.038 0.088 AD00632 0.781 0.048 0.858 0.101 AD00633 0.817 0.072 1.027 0.143 AD00634 0.807 0.087 0.978 0.256 AD00635 0.496 0.073 0.377 0.023 AD00636 0.615 0.102 0.748 0.072 AD00637 0.792 0.056 1.070 0.048

TABLE 5B In vitro analyses of LPA RNAi agents, inhibition of LPA expression. Relative R_(luc)-LPA expression Duplex 2 nM 0.2 nM 0.02 nM ID# Average SD Average SD Average SD AD01068 0.780 0.110 0.792 0.326 0.861 0.138 AD01069 0.483 0.345 1.062 0.181 0.869 0.112 AD01070 0.747 0.441 1.010 0.015 1.015 0.319 AD01071 1.014 0.254 0.850 0.251 0.857 0.284 AD01072 0.919 0.107 1.137 0.345 0.727 0.124 AD01073 0.539 0.224 1.066 0.195 1.180 0.356 AD01074 0.713 0.545 0.953 0.419 0.841 0.077 AD01075 0.703 0.379 0.913 0.204 0.965 0.216 AD01076 1.145 0.485 1.027 0.287 0.647 0.154 AD01077 0.672 0.074 1.166 0.384 0.703 0.106 AD01078 0.575 0.192 0.847 0.237 0.908 0.071 AD01079 0.863 0.673 1.093 0.187 1.004 0.086 AD01328 0.623 0.089 1.205 0.367 1.238 0.089 AD01329 0.467 0.068 1.161 0.159 1.115 0.102 AD01330 1.158 0.124 0.920 0.143 1.156 0.107 AD01331 1.476 0.225 1.092 0.269 1.304 0.320 AD01332 1.145 0.109 1.100 0.454 0.941 0.510 AD01333 0.829 0.011 1.382 0.252 1.338 0.303 AD01334 0.653 0.122 1.323 0.183 1.095 0.109 AD01335 0.858 0.089 1.632 0.318 1.201 0.159 AD01336 1.019 0.081 1.724 0.353 1.008 0.072 AD01337 0.834 0.143 1.494 0.657 1.130 0.309 AD01338 1.276 0.340 0.719 0.118 0.896 0.118 AD01339 1.240 0.298 1.114 0.287 0.960 0.104 AD01340 1.055 0.423 1.272 0.136 1.338 0.299 AD01341 1.206 0.438 1.510 0.315 1.046 0.143 AD01342 1.243 0.324 1.137 0.298 1.159 0.047 AD01343 1.113 0.140 1.045 0.151 1.108 0.094 AD01344 0.931 0.182 1.317 0.244 1.328 0.037 AD01345 0.795 0.233 0.799 0.032 1.418 0.184 AD01346 1.095 0.224 1.045 0.073 1.465 0.109 AD01347 1.122 0.021 1.209 0.161 1.153 0.159 AD01348 1.022 0.068 1.228 0.244 1.097 0.049 AD01349 0.934 0.151 1.217 0.080 1.068 0.149 AD01350 0.871 0.295 1.318 0.225 0.942 0.395 AD01351 1.414 0.065 1.121 0.180 1.029 0.049 AD01352 0.868 0.088 1.024 0.385 1.049 0.176 AD01353 1.150 0.478 1.164 0.276 0.898 0.175 AD01354 0.999 0.119 1.378 0.292 1.507 0.289 AD01355 0.943 0.092 1.066 0.268 1.411 0.113 AD01356 1.116 0.351 1.072 0.196 1.000 0.145

TABLE 5C In vitro analyses of 10 mM LPA RNAi agents, inhibition of LPA expression. Duplex No. LPA levels AD01803 0.77 ± 0.06 AD01805 0.77 ± 0.02 AD01806 1.01 ± 0.02 AD01807 0.97 ± 0.09 AD01808 0.78 ± 0.12 AD01809 1.06 ± 0.13 AD01810 1.06 ± 0.05 AD01811 0.86 ± 0.05 AD01812 1.08 ± 0.04 AD01813 0.99 ± 0.13 AD01814 0.57 ± 0.05 AD01815 0.65 ± 0.00 AD01816 0.84 ± 0.08 AD01817 0.75 ± 0.10 AD01818 0.94 ± 0.07 AD01819 1.21 ± 0.08 AD01820 1.22 ± 0.12 AD01821 1.16 ± 0.01 AD01822 1.22 ± 0.04 AD01823 0.91 ± 0.05 AD01824 1.22 ± 0.13 AD01825 1.25 ± 0.05 AD01826 1.18 ± 0.15 AD01827 1.23 ± 0.07 AD01828 1.02 ± 0.09 AD01829 1.05 ± 0.07 AD01830 1.00 ± 0.35 AD01831 1.02 ± 0.07 AD01832 1.04 ± 0.06 AD01896 0.71 ± 0.14 AD01897 0.87 ± 0.10 AD01898 1.16 ± 0.03 AD01899 0.79 ± 0.11 AD01900 0.82 ± 0.06 AD01901 0.54 ± 0.04 AD01902 0.62 ± 0.00 AD01903 0.66 ± 0.08 AD01912 0.59 ± 0.01 AD01913 0.60 ± 0.04 AD01914 0.50 ± 0.03 AD01915 0.58 ± 0.08 AD01916 0.49 ± 0.04 AD01917 0.53 ± 0.04 AD01918 0.47 ± 0.04 AD01919 0.60 ± 0.02 AD01920 0.60 ± 0.03 AD01921 0.59 ± 0.06 AD01922 0.50 ± 0.04 AD01923 0.59 ± 0.04 AD01924 0.50 ± 0.02 AD01925 0.54 ± 0.05 AD01926 0.52 ± 0.05 AD01927 0.57 ± 0.04 AD01928 0.50 ± 0.06 AD01929 0.55 ± 0.04 AD01930 0.54 ± 0.06 AD01931 0.54 ± 0.07 AD01932 0.51 ± 0.01 AD01933 0.56 ± 0.06 AD01934 0.52 ± 0.08 AD01935 0.58 ± 0.03 AD01936 0.53 ± 0.02 AD01937 0.57 ± 0.04 AD01938 0.58 ± 0.03 AD01939 0.65 ± 0.05 AD01940 0.49 ± 0.03 AD01941 0.57 ± 0.02

TABLE 5D In vitro analyses of 1 mM LPA RNAi agents, inhibition of LPA expression. Duplex LPA Duplex LPA Duplex LPA No. levels No. levels No. levels AD01760 0.10 ± 0.01 AD02330 0.37 ± 0.01 AD02090 0.68 ± 0.04 AD01722 0.14 ± 0.01 AD02243 0.37 ± 0.02 AD02161 0.68 ± 0.04 AD01757 0.15 ± 0.00 AD02255 0.38 ± 0.02 AD02324 0.68 ± 0.02 AD01719 0.15 ± 0.00 AD02257 0.38 ± 0.00 AD02177 0.69 ± 0.07 AD01738 0.18 ± 0.01 AD02169 0.38 ± 0.02 AD02179 0.69 ± 0.07 AD01755 0.19 ± 0.01 AD02081 0.38 ± 0.00 AD02527 0.69 ± 0.03 AD01741 0.20 ± 0.00 AD02186 0.38 ± 0.02 AD02305 0.69 ± 0.06 AD01759 0.23 ± 0.02 AD01744 0.38 ± 0.03 AD02092 0.70 ± 0.02 AD01747 0.23 ± 0.03 AD02075 0.38 ± 0.01 AD02535 0.70 ± 0.10 AD01752 0.24 ± 0.03 AD02135 0.38 ± 0.03 AD02376 0.71 ± 0.04 AD01736 0.24 ± 0.02 AD02114 0.38 ± 0.04 AD01743 0.71 ± 0.02 AD02311 0.25 ± 0.05 AD02188 0.38 ± 0.04 AD02289 0.71 ± 0.04 AD02201 0.25 ± 0.03 AD02318 0.38 ± 0.02 AD02530 0.71 ± 0.06 AD01750 0.25 ± 0.00 AD02388 0.38 ± 0.02 AD01709 0.71 ± 0.12 AD01756 0.25 ± 0.01 AD02115 0.38 ± 0.04 AD02249 0.71 ± 0.06 AD02291 0.25 ± 0.03 AD02133 0.38 ± 0.00 AD02534 0.71 ± 0.03 AD02292 0.26 ± 0.01 AD02183 0.38 ± 0.04 AD02213 0.71 ± 0.02 AD02266 0.26 ± 0.02 AD02116 0.38 ± 0.02 AD02529 0.71 ± 0.03 AD01763 0.26 ± 0.01 AD02132 0.39 ± 0.03 AD01711 0.71 ± 0.06 AD02259 0.26 ± 0.03 AD02400 0.39 ± 0.02 AD02341 0.72 ± 0.06 AD02327 0.26 ± 0.02 AD02338 0.39 ± 0.04 AD02233 0.72 ± 0.06 AD02274 0.27 ± 0.03 AD02112 0.39 ± 0.01 AD02342 0.73 ± 0.04 AD02297 0.27 ± 0.02 AD02354 0.39 ± 0.05 AD02395 0.73 ± 0.06 AD02147 0.27 ± 0.03 AD01749 0.40 ± 0.06 AD02306 0.73 ± 0.09 AD02365 0.27 ± 0.04 AD02312 0.40 ± 0.02 AD02344 0.73 ± 0.04 AD02260 0.27 ± 0.03 AD02240 0.40 ± 0.00 AD02145 0.74 ± 0.09 AD02368 0.27 ± 0.01 AD02313 0.40 ± 0.03 AD02326 0.74 ± 0.06 AD02265 0.28 ± 0.03 AD01710 0.40 ± 0.05 AD02414 0.74 ± 0.04 AD02293 0.28 ± 0.04 AD02301 0.40 ± 0.05 AD02379 0.74 ± 0.06 AD02350 0.28 ± 0.02 AD02425 0.40 ± 0.04 AD02532 0.75 ± 0.04 AD02202 0.28 ± 0.03 AD02099 0.41 ± 0.04 AD02178 0.75 ± 0.11 AD02203 0.28 ± 0.03 AD01723 0.41 ± 0.04 AD02195 0.75 ± 0.05 AD02258 0.28 ± 0.05 AD02391 0.41 ± 0.03 AD02123 0.76 ± 0.07 AD02295 0.28 ± 0.03 AD02392 0.41 ± 0.05 AD02164 0.77 ± 0.09 AD02363 0.28 ± 0.04 AD02083 0.41 ± 0.01 AD01726 0.77 ± 0.01 AD02273 0.28 ± 0.02 AD02155 0.41 ± 0.02 AD02231 0.77 ± 0.05 AD02386 0.28 ± 0.02 AD02082 0.41 ± 0.01 AD02180 0.77 ± 0.04 AD02309 0.28 ± 0.03 AD02336 0.41 ± 0.01 AD02412 0.77 ± 0.05 AD02382 0.29 ± 0.01 AD02101 0.41 ± 0.02 AD02251 0.77 ± 0.02 AD02256 0.29 ± 0.02 AD01728 0.42 ± 0.01 AD02396 0.78 ± 0.13 AD02367 0.29 ± 0.03 AD02424 0.42 ± 0.04 AD02160 0.78 ± 0.04 AD02275 0.29 ± 0.04 AD02175 0.42 ± 0.02 AD02533 0.78 ± 0.05 AD02206 0.29 ± 0.01 AD02225 0.42 ± 0.05 AD02290 0.78 ± 0.03 AD02332 0.29 ± 0.02 AD02086 0.43 ± 0.02 AD02378 0.78 ± 0.07 AD01717 0.29 ± 0.03 AD01725 0.43 ± 0.06 AD02394 0.79 ± 0.04 AD02296 0.29 ± 0.01 AD02374 0.43 ± 0.03 AD02415 0.79 ± 0.05 AD02264 0.29 ± 0.03 AD02390 0.43 ± 0.04 AD02181 0.79 ± 0.08 AD02278 0.29 ± 0.03 AD02227 0.43 ± 0.02 AD02492 0.79 ± 0.06 AD02385 0.29 ± 0.00 AD02137 0.43 ± 0.06 AD02397 0.79 ± 0.05 AD02205 0.29 ± 0.04 AD02085 0.43 ± 0.01 AD02398 0.79 ± 0.09 AD02149 0.29 ± 0.02 AD02407 0.43 ± 0.03 AD02416 0.79 ± 0.04 AD02239 0.30 ± 0.05 AD02100 0.44 ± 0.04 AD02144 0.79 ± 0.09 AD01748 0.30 ± 0.02 AD02406 0.44 ± 0.04 AD02531 0.79 ± 0.06 AD02404 0.30 ± 0.01 AD02136 0.44 ± 0.02 AD02489 0.80 ± 0.04 AD01721 0.30 ± 0.03 AD02209 0.44 ± 0.03 AD02307 0.80 ± 0.10 AD02277 0.30 ± 0.05 AD02154 0.44 ± 0.02 AD02308 0.80 ± 0.11 AD02152 0.30 ± 0.01 AD02171 0.44 ± 0.01 AD02182 0.80 ± 0.08 AD02237 0.30 ± 0.02 AD02261 0.45 ± 0.02 AD02198 0.80 ± 0.11 AD02098 0.30 ± 0.03 AD02271 0.45 ± 0.00 AD02199 0.80 ± 0.10 AD02381 0.30 ± 0.02 AD02371 0.45 ± 0.03 AD02200 0.80 ± 0.06 AD02315 0.30 ± 0.02 AD02173 0.45 ± 0.07 AD02125 0.81 ± 0.06 AD02366 0.30 ± 0.01 AD02319 0.45 ± 0.01 AD02141 0.81 ± 0.01 AD02242 0.31 ± 0.03 AD02176 0.46 ± 0.01 AD02516 0.81 ± 0.06 AD02294 0.31 ± 0.02 AD02428 0.46 ± 0.02 AD02127 0.81 ± 0.06 AD02346 0.31 ± 0.04 AD02410 0.46 ± 0.01 AD02380 0.81 ± 0.03 AD02329 0.31 ± 0.02 AD01746 0.46 ± 0.05 AD02124 0.81 ± 0.05 AD02348 0.31 ± 0.01 AD01732 0.46 ± 0.02 AD02197 0.81 ± 0.02 AD01714 0.31 ± 0.05 AD02157 0.47 ± 0.02 AD02159 0.81 ± 0.09 AD01724 0.31 ± 0.01 AD02372 0.47 ± 0.03 AD02485 0.82 ± 0.04 AD02170 0.31 ± 0.02 AD02427 0.47 ± 0.02 AD02142 0.82 ± 0.08 AD02352 0.31 ± 0.02 AD02370 0.47 ± 0.01 AD02126 0.82 ± 0.08 AD02093 0.31 ± 0.01 AD02172 0.47 ± 0.04 AD02254 0.82 ± 0.10 AD02383 0.31 ± 0.02 AD02158 0.47 ± 0.02 AD02232 0.82 ± 0.04 AD02284 0.31 ± 0.04 AD02270 0.48 ± 0.04 AD02146 0.82 ± 0.04 AD02219 0.31 ± 0.04 AD02426 0.48 ± 0.04 AD02490 0.82 ± 0.03 AD02279 0.31 ± 0.03 AD02361 0.48 ± 0.04 AD01745 0.82 ± 0.09 AD02299 0.31 ± 0.05 AD02245 0.48 ± 0.02 AD02162 0.83 ± 0.04 AD01740 0.31 ± 0.02 AD02373 0.48 ± 0.01 AD02471 0.83 ± 0.11 AD02417 0.32 ± 0.01 AD02084 0.48 ± 0.05 AD02487 0.83 ± 0.09 AD02364 0.32 ± 0.02 AD02194 0.48 ± 0.03 AD02523 0.83 ± 0.10 AD02262 0.32 ± 0.03 AD01753 0.48 ± 0.06 AD02483 0.83 ± 0.03 AD02369 0.32 ± 0.01 AD02320 0.48 ± 0.03 AD02128 0.84 ± 0.09 AD01731 0.32 ± 0.02 AD02268 0.48 ± 0.05 AD02143 0.84 ± 0.05 AD02349 0.32 ± 0.01 AD02226 0.49 ± 0.01 AD02214 0.84 ± 0.13 AD02095 0.32 ± 0.02 AD02156 0.49 ± 0.01 AD02217 0.84 ± 0.07 AD02281 0.32 ± 0.01 AD02409 0.49 ± 0.03 AD02250 0.84 ± 0.08 AD02224 0.32 ± 0.06 AD02244 0.49 ± 0.02 AD02163 0.85 ± 0.04 AD02148 0.32 ± 0.04 AD02189 0.49 ± 0.06 AD02525 0.85 ± 0.06 AD01718 0.33 ± 0.01 AD01764 0.50 ± 0.02 AD02481 0.85 ± 0.03 AD02333 0.33 ± 0.01 AD02174 0.50 ± 0.04 AD02235 0.85 ± 0.03 AD02403 0.33 ± 0.01 AD02117 0.50 ± 0.01 AD02539 0.86 ± 0.05 AD02317 0.33 ± 0.03 AD02208 0.50 ± 0.05 AD02470 0.86 ± 0.07 AD02399 0.33 ± 0.02 AD02104 0.51 ± 0.03 AD02469 0.86 ± 0.04 AD02222 0.33 ± 0.01 AD02408 0.51 ± 0.06 AD02480 0.86 ± 0.07 AD02310 0.33 ± 0.02 AD02272 0.51 ± 0.04 AD02488 0.87 ± 0.05 AD01733 0.33 ± 0.01 AD02122 0.51 ± 0.06 AD02511 0.87 ± 0.05 AD02131 0.33 ± 0.01 AD02140 0.51 ± 0.04 AD02482 0.87 ± 0.04 AD02353 0.33 ± 0.03 AD02362 0.51 ± 0.04 AD02519 0.87 ± 0.08 AD02263 0.33 ± 0.03 AD01739 0.52 ± 0.04 AD02491 0.88 ± 0.05 AD02204 0.33 ± 0.01 AD02121 0.52 ± 0.06 AD02216 0.88 ± 0.00 AD02080 0.33 ± 0.00 AD02138 0.52 ± 0.04 AD02215 0.88 ± 0.03 AD02298 0.33 ± 0.03 AD02358 0.52 ± 0.02 AD02468 0.88 ± 0.06 AD01737 0.33 ± 0.01 AD01734 0.53 ± 0.06 AD02526 0.88 ± 0.06 AD02220 0.33 ± 0.04 AD01713 0.53 ± 0.04 AD02234 0.88 ± 0.14 AD02302 0.33 ± 0.00 AD02285 0.53 ± 0.03 AD02518 0.89 ± 0.05 AD02097 0.33 ± 0.00 AD02102 0.53 ± 0.07 AD02218 0.89 ± 0.04 AD02328 0.33 ± 0.02 AD02303 0.53 ± 0.03 AD02515 0.89 ± 0.03 AD02221 0.33 ± 0.01 AD02212 0.53 ± 0.01 AD02536 0.89 ± 0.11 AD02421 0.33 ± 0.02 AD02139 0.53 ± 0.03 AD02537 0.89 ± 0.04 AD02420 0.33 ± 0.03 AD02230 0.54 ± 0.08 AD02465 0.89 ± 0.07 AD02347 0.33 ± 0.04 AD02103 0.54 ± 0.04 AD02196 0.90 ± 0.03 AD02134 0.34 ± 0.01 AD02191 0.54 ± 0.03 AD02253 0.90 ± 0.05 AD02078 0.34 ± 0.03 AD02429 0.54 ± 0.02 AD02484 0.90 ± 0.09 AD02151 0.34 ± 0.02 AD01716 0.54 ± 0.09 AD02467 0.91 ± 0.00 AD02238 0.34 ± 0.03 AD02360 0.54 ± 0.02 AD02538 0.91 ± 0.10 AD02168 0.34 ± 0.00 AD01762 0.54 ± 0.01 AD02478 0.91 ± 0.01 AD02096 0.34 ± 0.03 AD01735 0.55 ± 0.07 AD02479 0.92 ± 0.05 AD01758 0.34 ± 0.05 AD02248 0.55 ± 0.05 AD02540 0.92 ± 0.08 AD02077 0.34 ± 0.02 AD02193 0.55 ± 0.01 AD02524 0.92 ± 0.03 AD02345 0.34 ± 0.02 AD02119 0.55 ± 0.01 AD02466 0.92 ± 0.05 AD02384 0.34 ± 0.02 AD02287 0.55 ± 0.02 AD02520 0.92 ± 0.06 AD02094 0.34 ± 0.01 AD02357 0.56 ± 0.01 AD02498 0.92 ± 0.06 AD02419 0.34 ± 0.04 AD01708 0.57 ± 0.06 AD02472 0.92 ± 0.05 AD02401 0.34 ± 0.02 AD02247 0.57 ± 0.06 AD02106 0.93 ± 0.08 AD02402 0.34 ± 0.03 AD02430 0.58 ± 0.07 AD02486 0.93 ± 0.02 AD01712 0.34 ± 0.04 AD02339 0.58 ± 0.03 AD02236 0.93 ± 0.04 AD02276 0.34 ± 0.01 AD02321 0.59 ± 0.03 AD02543 0.93 ± 0.12 AD02150 0.34 ± 0.02 AD02269 0.59 ± 0.02 AD02517 0.94 ± 0.05 AD02166 0.34 ± 0.03 AD02210 0.59 ± 0.04 AD02505 0.94 ± 0.10 AD02351 0.34 ± 0.02 AD02211 0.60 ± 0.02 AD02464 0.94 ± 0.06 AD02241 0.35 ± 0.04 AD02091 0.60 ± 0.03 AD02499 0.94 ± 0.16 AD02282 0.35 ± 0.01 AD02120 0.60 ± 0.07 AD02500 0.94 ± 0.05 AD02130 0.35 ± 0.04 AD02229 0.60 ± 0.03 AD02544 0.95 ± 0.07 AD01751 0.35 ± 0.03 AD01727 0.60 ± 0.02 AD02541 0.95 ± 0.15 AD02356 0.35 ± 0.03 AD01730 0.60 ± 0.02 AD02509 0.95 ± 0.09 AD02405 0.35 ± 0.04 AD02190 0.60 ± 0.07 AD02508 0.95 ± 0.10 AD02129 0.35 ± 0.01 AD02411 0.60 ± 0.06 AD02510 0.95 ± 0.03 AD02355 0.35 ± 0.01 AD02322 0.61 ± 0.03 AD02521 0.96 ± 0.16 AD02423 0.35 ± 0.06 AD02433 0.61 ± 0.02 AD02507 0.96 ± 0.03 AD02316 0.35 ± 0.02 AD01761 0.62 ± 0.05 AD02105 0.96 ± 0.09 AD02331 0.35 ± 0.02 AD01720 0.62 ± 0.02 AD02495 0.96 ± 0.05 AD02335 0.35 ± 0.01 AD02228 0.62 ± 0.06 AD02504 0.97 ± 0.04 AD02187 0.35 ± 0.03 AD02393 0.62 ± 0.03 AD02493 0.97 ± 0.06 AD02314 0.36 ± 0.04 AD02359 0.62 ± 0.03 AD02542 0.97 ± 0.06 AD02300 0.36 ± 0.03 AD02323 0.62 ± 0.05 AD02503 0.98 ± 0.05 AD02387 0.36 ± 0.06 AD02118 0.63 ± 0.05 AD02107 0.98 ± 0.05 AD02337 0.36 ± 0.04 AD02286 0.63 ± 0.04 AD02477 0.98 ± 0.06 AD01729 0.36 ± 0.01 AD02087 0.63 ± 0.04 AD02501 0.98 ± 0.07 AD02283 0.36 ± 0.02 AD01715 0.63 ± 0.06 AD02497 0.98 ± 0.05 AD02185 0.36 ± 0.01 AD02192 0.63 ± 0.02 AD02494 0.98 ± 0.13 AD02167 0.36 ± 0.01 AD02431 0.64 ± 0.06 AD02475 1.00 ± 0.07 AD02076 0.36 ± 0.04 AD02340 0.64 ± 0.03 AD02514 1.00 ± 0.00 AD02418 0.36 ± 0.01 AD02432 0.64 ± 0.02 AD02474 1.00 ± 0.03 AD02422 0.36 ± 0.03 AD02089 0.65 ± 0.07 AD02502 1.01 ± 0.01 AD02111 0.36 ± 0.02 AD02267 0.65 ± 0.11 AD02522 1.01 ± 0.04 AD02079 0.37 ± 0.02 AD02246 0.65 ± 0.07 AD02476 1.01 ± 0.09 AD01754 0.37 ± 0.04 AD02325 0.65 ± 0.03 AD02513 1.02 ± 0.03 AD02334 0.37 ± 0.02 AD02343 0.66 ± 0.05 AD02109 1.02 ± 0.06 AD02280 0.37 ± 0.05 AD02375 0.66 ± 0.04 AD02252 1.02 ± 0.08 AD02113 0.37 ± 0.03 AD02288 0.66 ± 0.06 AD02496 1.04 ± 0.05 AD02389 0.37 ± 0.03 AD02088 0.66 ± 0.01 AD02473 1.05 ± 0.04 AD02223 0.37 ± 0.04 AD02413 0.66 ± 0.03 AD02506 1.05 ± 0.05 AD02184 0.37 ± 0.02 AD02377 0.67 ± 0.05 AD01742 1.07 ± 0.24 AD02153 0.37 ± 0.02 AD02528 0.67 ± 0.04 AD02110 1.08 ± 0.07 AD02165 0.37 ± 0.02 AD02434 0.67 ± 0.05 AD02512 1.09 ± 0.17 AD02207 0.37 ± 0.01 AD02304 0.67 ± 0.02 AD02108 1.11 ± 0.04

Example 3. LPA RNAi Agent EC₅₀ Determination

Ten-point EC₅₀ curves were generated using the same cells and transfection conditions, with LPA RNAi agent concentrations ranging from 150fM-3 nM. EC₅₀ were determined using GraphPad Prism software (Table 6).

TABLE 6 EC₅₀ values (nM) determined in vitro for the indicated LPA RNAi agents. Duplex ID# EC₅₀ (nM) AD00575 0.073 AD00576 0.038 AD00578 0.112 AD00579 0.083 AD00621 0.100 AD00635 0.577 AD01070 0.6388 AD01072 0.1068 AD01073 0.1154 AD01074 0.2903

Example 4. In Vitro Analysis of Structure-Activity Relationship (SAR) Designed LPA RNAi Agents

LPA RNAi agent SAR sets (364 sequences based on AD01532 and 351 sequences based on AD01533) were synthesized and screened for efficacy in vitro. For screening purposes, 2756 bp of the human LPA cDNA sequence from KIV-3 to KIV-9 (accession # NM_005577.1) was synthesized and cloned (GeneWiz, South Plainfield, N.J.) into a commercially-available, reporter-based screening plasmid, psiCHECK2 (Promega, Madison, Wis.) which generated a Renilla luciferase/LPA fusion mRNA. For LPA RNAi agent efficacy in the human background, HuH7 cells, a human hepatocellular carcinoma line, were plated at ˜7500 cells per well in 96-well format. Each of the LPA RNAi agents was co-transfected at two concentrations (1 nM and 0.1 nM, or 10 nM and 1 nM) with 25 ng LPA-psiCHECK2 plasmid DNA per well and 0.2 μL LipoFectamine 2000 per well. Gene knockdown was determined by measuring Renilla luciferase levels normalized to the levels of constitutively-expressed firefly luciferase, also present on the psiCHECK2 plasmid, using the Dual Luciferase Reporter Assay (Promega, Madison, Wis.) (Tables 7A and 7B).

TABLE 7A Efficacy screen results of LPA RNAi agents in vitro, as determined by dual-luciferase reporter assay. Relative R_(luc)-LPA Duplex expression ID No. 1 nM 0.1 nM SD0001 0.570 0.907 SD0002 0.873 1.061 SD0003 0.955 1.020 SD0004 0.845 1.007 SD0005 0.603 0.891 SD0006 0.551 0.780 SD0007 0.510 0.797 SD0008 0.544 0.892 SD0009 0.564 0.878 SD0010 0.542 1.051 SD0011 0.513 0.873 SD0012 0.533 0.963 SD0013 0.541 0.979 SD0014 0.551 0.987 SD0015 0.488 0.951 SD0016 0.588 0.868 SD0017 1.023 1.005 SD0018 0.866 0.965 SD0019 0.792 1.005 SD0020 0.633 0.860 SD0021 0.572 0.797 SD0022 0.610 0.874 SD0023 0.550 0.836 SD0024 0.597 0.859 SD0025 0.587 0.899 SD0026 0.570 0.898 SD0027 0.580 0.825 SD0028 0.612 0.885 SD0029 0.528 0.866 SD0030 0.657 0.825 SD0031 0.560 0.914 SD0032 0.664 0.976 SD0033 0.787 1.035 SD0034 0.739 1.002 SD0035 0.658 0.949 SD0036 0.554 0.896 SD0037 0.557 0.873 SD0038 0.528 0.854 SD0039 0.511 0.847 SD0040 0.554 0.976 SD0041 0.559 0.823 SD0042 0.496 0.825 SD0043 0.563 0.851 SD0044 0.476 0.861 SD0045 0.542 0.841 SD0046 0.651 0.980 SD0047 0.967 0.995 SD0048 0.694 0.936 SD0049 0.960 0.946 SD0050 0.692 0.971 SD0051 0.611 0.905 SD0052 0.657 0.849 SD0053 0.642 0.848 SD0054 0.598 0.852 SD0055 0.494 0.828 SD0056 0.524 0.885 SD0057 0.582 0.816 SD0058 0.597 0.866 SD0059 0.560 0.905 SD0060 0.594 0.849 SD0061 0.571 1.058 SD0062 0.871 1.157 SD0063 0.969 1.138 SD0064 0.555 1.019 SD0065 0.671 0.953 SD0066 0.561 0.951 SD0067 0.612 0.904 SD0068 0.573 0.938 SD0069 0.574 0.975 SD0070 0.606 1.030 SD0071 0.494 0.959 SD0072 0.557 0.892 SD0073 0.593 0.984 SD0074 0.544 0.894 SD0075 0.552 0.937 SD0076 0.513 1.058 SD0077 0.930 1.071 SD0078 0.984 1.006 SD0079 0.853 1.031 SD0080 0.577 0.942 SD0081 0.595 1.044 SD0082 0.652 0.962 SD0083 0.583 0.928 SD0084 0.540 1.049 SD0085 0.523 0.961 SD0086 0.536 0.956 SD0087 0.586 0.987 SD0088 0.563 0.892 SD0089 0.555 0.947 SD0090 0.599 0.928 SD0091 0.665 0.854 SD0092 1.002 0.917 SD0093 1.047 0.880 SD0094 0.867 0.911 SD0095 0.919 0.868 SD0096 0.666 0.887 SD0097 0.673 0.737 SD0098 0.567 0.809 SD0099 0.604 0.909 SD0100 0.557 0.880 SD0101 0.545 0.806 SD0102 0.728 0.900 SD0103 0.719 0.928 SD0104 0.766 0.955 SD0105 0.965 0.927 SD0106 1.161 1.006 SD0107 1.048 0.966 SD0108 1.066 0.985 SD0109 1.111 0.917 SD0110 1.152 0.954 SD0111 1.045 0.944 SD0112 1.089 1.019 SD0113 0.949 0.935 SD0114 0.875 1.033 SD0115 1.022 1.077 SD0116 0.947 1.028 SD0117 0.946 1.021 SD0118 0.879 0.977 SD0119 0.963 1.016 SD0120 0.967 0.948 SD0121 0.651 0.897 SD0122 1.085 1.111 SD0123 1.153 1.052 SD0124 0.955 0.936 SD0125 0.928 0.928 SD0126 1.033 0.933 SD0127 0.637 0.717 SD0128 0.630 0.653 SD0129 1.052 1.192 SD0130 1.025 1.107 SD0131 1.280 1.059 SD0132 1.094 1.024 SD0133 1.113 1.031 SD0134 0.928 0.991 SD0135 0.804 1.023 SD0136 1.028 1.104 SD0137 0.902 1.149 SD0138 0.942 1.015 SD0139 0.984 1.068 SD0140 0.953 1.091 SD0141 0.925 1.022 SD0142 0.906 0.994 SD0143 0.898 0.990 SD0144 0.858 0.972 SD0145 0.917 0.947 SD0146 0.850 0.906 SD0147 0.933 0.995 SD0148 0.856 0.994 SD0149 0.882 0.985 SD0150 0.810 1.002 SD0151 0.813 0.909 SD0152 0.963 1.031 SD0153 1.058 0.936 SD0154 0.968 0.944 SD0155 0.969 0.940 SD0156 0.933 0.807 SD0157 0.906 0.913 SD0158 0.926 0.964 SD0159 0.805 0.850 SD0160 0.895 0.965 SD0161 0.865 1.006 SD0162 0.935 1.029 SD0163 0.928 0.985 SD0164 0.920 0.957 SD0165 1.039 1.110 SD0166 1.061 1.023 SD0167 1.020 0.982 SD0168 1.053 0.989 SD0169 1.002 1.018 SD0170 1.078 0.982 SD0171 0.838 0.923 SD0172 1.025 0.934 SD0173 0.864 0.963 SD0174 1.020 1.043 SD0175 1.128 1.046 SD0176 1.009 1.110 SD0177 0.735 0.975 SD0178 0.824 1.074 SD0179 0.690 0.895 SD0180 0.572 0.914 SD0181 0.904 1.028 SD0182 1.176 1.093 SD0183 1.247 1.090 SD0184 1.097 0.974 SD0185 1.045 0.985 SD0186 0.940 0.943 SD0187 0.883 0.994 SD0188 ND ND SD0189 0.872 0.977 SD0190 0.861 1.166 SD0191 0.779 1.044 SD0192 0.796 1.116 SD0193 0.975 1.112 SD0194 0.876 1.058 SD0195 0.747 0.970 SD0196 0.787 1.086 SD0197 1.276 1.127 SD0198 1.144 1.140 SD0199 1.136 1.101 SD0200 0.814 0.911 SD0201 0.733 0.915 SD0202 0.576 0.933 SD0203 0.593 0.824 SD0204 0.882 1.038 SD0205 0.681 1.012 SD0206 0.600 0.927 SD0207 0.738 0.974 SD0208 0.638 0.883 SD0209 0.641 0.878 SD0210 0.544 0.886 SD0211 0.702 0.920 SD0212 0.704 0.854 SD0213 0.655 0.887 SD0214 0.629 0.860 SD0215 0.598 0.850 SD0216 0.611 0.782 SD0217 0.710 0.806 SD0218 0.738 0.758 SD0219 0.664 0.809 SD0220 1.133 0.891 SD0221 0.940 0.914 SD0222 0.853 0.882 SD0223 0.691 0.889 SD0224 0.997 1.033 SD0225 0.954 0.998 SD0226 1.202 0.997 SD0227 0.948 1.017 SD0228 0.786 0.947 SD0229 0.620 0.830 SD0230 0.840 0.972 SD0231 0.904 0.890

TABLE 7B Efficacy screen results of LPA RNAi agents in vitro, as determined by dual-luciferase reporter assay. Relative R_(luc)-LPA Duplex expression ID # 10 nM 1 nM SD0232 0.659 0.699 SD0233 0.942 1.252 SD0234 0.967 1.358 SD0235 0.910 0.890 SD0236 0.742 0.822 SD0237 0.758 0.831 SD0238 0.700 0.737 SD0239 0.645 0.765 SD0240 0.701 0.773 SD0241 0.770 0.821 SD0242 0.626 0.719 SD0243 0.759 0.848 SD0244 0.798 0.953 SD0245 0.764 0.821 SD0246 0.812 0.690 SD0247 0.786 0.844 SD0248 1.011 1.167 SD0249 1.118 1.189 SD0250 1.021 1.239 SD0251 1.041 1.151 SD0252 1.070 1.124 SD0253 1.044 1.131 SD0254 0.861 0.948 SD0255 0.751 0.829 SD0256 0.931 1.037 SD0257 1.024 1.037 SD0258 0.935 1.030 SD0259 1.089 1.081 SD0260 0.955 1.008 SD0261 0.923 0.980 SD0262 0.908 1.107 SD0263 1.060 1.449 SD0264 1.041 1.419 SD0265 1.065 1.373 SD0266 0.950 1.376 SD0267 0.963 1.214 SD0268 1.023 1.299 SD0269 0.908 1.066 SD0270 0.963 1.081 SD0271 1.088 1.189 SD0272 0.966 1.135 SD0273 0.953 1.192 SD0274 1.049 1.217 SD0275 1.006 1.206 SD0276 0.969 1.064 SD0277 0.686 0.796 SD0278 0.985 1.305 SD0279 0.985 1.301 SD0280 0.978 1.237 SD0281 1.038 1.230 SD0282 0.933 1.191 SD0283 0.930 1.152 SD0284 0.907 1.117 SD0285 0.625 0.870 SD0286 0.984 1.056 SD0287 0.906 0.965 SD0288 1.052 1.123 SD0289 0.997 1.215 SD0290 0.892 1.197 SD0291 0.907 1.065 SD0292 0.689 0.862 SD0293 0.955 1.190 SD0294 1.095 1.157 SD0295 0.851 1.004 SD0296 1.018 1.106 SD0297 0.737 0.760 SD0298 0.790 0.828 SD0299 0.721 0.713 SD0300 0.796 0.869 SD0301 0.781 0.841 SD0302 0.621 0.720 SD0303 0.684 0.852 SD0304 0.774 0.842 SD0305 0.778 0.799 SD0306 0.718 0.793 SD0307 0.982 0.883 SD0308 1.297 1.193 SD0309 1.123 1.208 SD0310 0.961 1.073 SD0311 1.168 1.019 SD0312 0.923 0.824 SD0313 0.883 0.871 SD0314 0.670 0.650 SD0315 0.988 0.958 SD0316 0.908 0.880 SD0317 0.754 0.850 SD0318 0.963 0.944 SD0319 0.945 0.862 SD0320 0.961 0.875 SD0321 0.841 0.797 SD0322 0.546 0.521 SD0323 0.581 0.895 SD0324 0.692 0.900 SD0325 0.506 0.796 SD0326 0.634 0.709 SD0327 0.522 0.592 SD0328 0.602 0.632 SD0329 0.504 0.615 SD0330 0.445 0.601 SD0331 0.457 0.579 SD0332 0.500 0.601 SD0333 0.447 0.618 SD0334 0.490 0.528 SD0335 0.421 0.555 SD0336 0.488 0.533 SD0337 1.714 0.978 SD0338 1.262 1.350 SD0339 1.259 1.357 SD0340 0.996 1.277 SD0341 1.190 1.183 SD0342 0.818 0.923 SD0343 0.803 0.855 SD0344 0.708 0.883 SD0345 1.132 0.901 SD0346 0.847 0.890 SD0347 0.659 0.780 SD0348 0.730 0.945 SD0349 0.825 0.886 SD0350 0.826 0.897 SD0351 0.730 0.842 SD0352 0.297 0.276 SD0353 0.773 0.746 SD0354 0.663 0.722 SD0355 0.620 0.626 SD0356 0.546 0.599 SD0357 0.298 0.411 SD0358 0.313 0.318 SD0359 0.273 0.282 SD0360 0.256 0.257 SD0361 0.269 0.276 SD0362 0.270 0.276 SD0363 0.350 0.272 SD0364 0.227 0.243 SD0365 0.228 0.233 SD0366 0.264 0.241 SD0367 0.262 0.252 SD0368 0.571 0.597 SD0369 0.539 0.531 SD0370 0.521 0.545 SD0371 0.302 0.319 SD0372 0.353 0.335 SD0373 0.279 0.255 SD0374 0.266 0.194 SD0375 0.246 0.238 SD0376 0.258 0.238 SD0377 0.246 0.226 SD0378 0.237 0.226 SD0379 0.262 0.226 SD0380 0.247 0.240 SD0381 0.639 0.657 SD0382 0.267 0.517 SD0383 0.473 0.547 SD0384 0.456 0.563 SD0385 0.264 0.393 SD0386 0.329 0.325 SD0387 0.186 0.231 SD0388 0.217 0.248 SD0389 0.230 0.275 SD0390 0.210 0.270 SD0391 0.247 0.224 SD0392 0.257 0.236 SD0393 0.252 0.253 SD0394 0.267 0.251 SD0395 0.594 0.675 SD0396 0.511 0.678 SD0397 0.457 0.618 SD0398 0.516 0.601 SD0399 0.261 0.389 SD0400 0.327 0.300 SD0401 0.230 0.250 SD0402 0.231 0.260 SD0403 0.237 0.221 SD0404 0.258 0.243 SD0405 0.253 0.246 SD0406 0.228 0.230 SD0407 0.228 0.215 SD0408 0.247 0.255 SD0409 0.565 0.667 SD0410 0.796 0.863 SD0411 0.633 0.646 SD0412 0.613 0.699 SD0413 0.294 0.439 SD0414 0.416 0.310 SD0415 0.275 0.238 SD0416 0.241 0.290 SD0417 0.257 0.284 SD0418 0.267 0.306 SD0419 0.249 0.229 SD0420 0.243 0.240 SD0421 0.250 0.241 SD0422 0.230 0.237 SD0423 0.555 0.684 SD0424 0.614 0.682 SD0425 0.592 0.733 SD0426 0.604 0.699 SD0427 0.281 0.449 SD0428 0.301 0.330 SD0429 0.230 0.261 SD0430 0.241 0.273 SD0431 0.232 0.255 SD0432 0.247 0.288 SD0433 0.238 0.280 SD0434 0.224 0.293 SD0435 0.249 0.240 SD0436 0.428 0.445 SD0437 0.542 0.829 SD0438 1.106 1.048 SD0439 0.930 1.096 SD0440 1.033 1.023 SD0441 0.630 0.657 SD0442 0.912 0.913 SD0443 0.392 0.375 SD0444 0.552 0.441 SD0445 0.561 0.514 SD0446 0.550 0.442 SD0447 0.415 0.362 SD0448 0.566 0.503 SD0449 0.579 0.475 SD0450 0.463 0.424 SD0451 0.925 0.929 SD0452 0.963 0.939 SD0453 0.967 0.952 SD0454 0.948 0.883 SD0455 0.746 0.645 SD0456 0.840 0.860 SD0457 0.473 0.402 SD0458 0.555 0.514 SD0459 0.566 0.472 SD0460 0.609 0.478 SD0461 0.408 0.355 SD0462 0.630 0.532 SD0463 0.631 0.497 SD0464 0.549 0.510 SD0465 0.966 0.809 SD0466 0.910 0.841 SD0467 0.904 0.878 SD0468 0.999 1.009 SD0469 0.734 0.760 SD0470 0.925 0.806 SD0471 0.559 0.482 SD0472 0.572 0.543 SD0473 0.652 0.594 SD0474 0.621 0.598 SD0475 0.564 0.472 SD0476 0.769 0.631 SD0477 0.734 0.613 SD0478 0.460 0.411 SD0479 0.713 0.802 SD0480 0.883 0.892 SD0481 0.926 0.899 SD0482 1.180 0.937 SD0483 0.805 0.986 SD0484 0.920 1.104 SD0485 0.510 0.524 SD0486 0.626 0.598 SD0487 0.628 0.640 SD0488 0.597 0.637 SD0489 0.482 0.486 SD0490 0.685 0.664 SD0491 0.650 0.662 SD0492 0.454 0.490 SD0493 1.006 1.040 SD0494 0.933 1.024 SD0495 0.927 1.016 SD0496 0.921 1.004 SD0497 0.690 0.846 SD0498 0.970 0.913 SD0499 0.448 0.399 SD0500 0.614 0.485 SD0501 0.609 0.521 SD0502 0.626 0.526 SD0503 0.493 0.410 SD0504 0.727 0.551 SD0505 0.688 0.541 SD0506 0.319 0.338 SD0507 0.927 0.897 SD0508 0.929 0.972 SD0509 0.853 0.925 SD0510 0.755 0.935 SD0511 0.480 0.559 SD0512 0.834 0.854 SD0513 0.440 0.323 SD0514 0.415 0.414 SD0515 0.442 0.343 SD0516 0.422 0.341 SD0517 0.346 0.320 SD0518 0.488 0.420 SD0519 0.435 0.390 SD0520 0.819 0.737 SD0521 1.058 0.903 SD0522 1.088 0.933 SD0523 1.075 0.948 SD0524 1.067 0.900 SD0525 0.917 0.858 SD0526 1.126 1.055 SD0527 0.832 0.776 SD0528 0.980 0.886 SD0529 1.059 0.821 SD0530 0.934 0.844 SD0531 0.832 0.883 SD0532 0.936 0.868 SD0533 0.900 0.946 SD0534 1.012 0.984 SD0535 1.041 1.095 SD0536 1.113 1.097 SD0537 1.125 0.957 SD0538 1.059 1.162 SD0539 0.901 0.963 SD0540 0.900 0.924 SD0541 1.033 0.911 SD0542 0.958 0.906 SD0543 0.870 0.816 SD0544 1.100 0.853 SD0545 0.881 0.794 SD0546 0.897 0.813 SD0547 1.005 0.785 SD0548 0.972 0.866 SD0549 1.019 1.121 SD0550 0.986 1.015 SD0551 0.966 1.033 SD0552 0.893 1.028 SD0553 0.976 0.998 SD0554 0.938 0.935 SD0555 0.886 0.875 SD0556 1.181 1.142 SD0557 1.016 0.999 SD0558 1.026 0.968 SD0559 0.928 0.844 SD0560 0.990 0.805 SD0561 0.836 0.791 SD0562 1.021 0.772 SD0563 0.886 0.946 SD0564 1.194 1.254 SD0565 1.010 1.033 SD0566 1.110 0.993 SD0567 0.995 0.895 SD0568 0.964 0.901 SD0569 0.853 0.876 SD0570 0.832 0.860 SD0571 1.036 0.959 SD0572 1.013 0.902 SD0573 0.948 0.793 SD0574 0.868 0.812 SD0575 0.946 0.712 SD0576 0.922 0.774 SD0577 0.824 0.800 SD0578 0.997 0.950 SD0579 1.048 1.143 SD0580 1.071 0.935 SD0581 0.987 0.869 SD0582 0.946 0.816 SD0583 0.932 0.789 SD0584 1.062 0.866 SD0585 1.155 0.891 SD0586 0.960 0.819 SD0587 0.934 0.832 SD0588 1.033 0.781 SD0589 0.972 0.798 SD0590 0.925 0.704 SD0591 1.061 0.915 SD0592 1.129 0.996 SD0593 0.856 0.895 SD0594 0.840 0.956 SD0595 0.882 0.857 SD0596 0.856 0.896 SD0597 0.869 0.697 SD0598 0.878 0.700 SD0599 0.808 0.857 SD0600 0.856 0.823 SD0601 0.742 0.713 SD0602 0.740 0.846 SD0603 0.808 0.816 SD0604 0.561 0.527 SD0605 0.711 0.880 SD0606 0.852 0.922 SD0607 0.695 0.887 SD0608 0.635 0.917 SD0609 0.655 0.874 SD0610 0.596 0.765 SD0611 0.482 0.508 SD0612 0.629 0.578 SD0613 0.616 0.503 SD0614 0.716 0.682 SD0615 0.570 0.491 SD0616 0.671 0.668 SD0617 0.713 0.721 SD0618 0.819 0.862 SD0619 0.925 0.968 SD0620 0.859 0.978 SD0621 0.923 1.075 SD0622 0.900 0.988 SD0623 0.908 0.969 SD0624 0.775 0.889 SD0625 0.827 0.850 SD0626 0.832 0.796 SD0627 0.916 0.796 SD0628 0.863 0.898 SD0629 0.915 0.869 SD0630 0.893 0.856 SD0631 0.940 0.848 SD0632 0.878 0.911 SD0633 0.934 1.074 SD0634 0.915 1.019 SD0635 0.911 0.912 SD0636 0.852 0.911 SD0637 0.997 0.965 SD0638 0.983 0.935 SD0639 0.806 0.823 SD0640 0.838 0.846 SD0641 0.906 0.861 SD0642 0.740 0.836 SD0643 0.739 0.725 SD0644 0.780 0.762 SD0645 0.739 0.819 SD0646 0.734 0.798 SD0647 0.789 0.913 SD0648 0.707 0.946 SD0649 0.943 1.077 SD0650 0.729 0.872 SD0651 0.666 0.879 SD0652 0.704 0.882 SD0653 0.661 0.726 SD0654 0.751 0.881 SD0655 0.727 0.822 SD0656 0.746 0.839 SD0657 0.849 0.842 SD0658 0.835 0.796 SD0659 0.972 0.830 SD0660 0.772 0.672 SD0661 0.883 0.918 SD0662 0.934 0.952 SD0663 0.974 0.891 SD0664 0.939 0.936 SD0665 1.116 0.919 SD0666 0.924 0.954 SD0667 0.780 0.744 SD0668 0.795 0.726 SD0669 0.819 0.754 SD0670 0.856 0.830 SD0671 0.844 0.758 SD0672 0.978 0.952 SD0673 0.860 0.845 SD0674 0.526 0.566 SD0675 0.661 0.961 SD0676 0.690 0.916 SD0677 0.672 0.939 SD0678 0.821 0.973 SD0679 0.943 0.952 SD0680 1.018 0.991 SD0681 0.561 0.580 SD0682 0.777 0.688 SD0683 0.654 0.639 SD0684 0.691 0.622 SD0685 0.518 0.555 SD0686 0.661 0.738 SD0687 0.722 0.644 SD0688 0.416 0.385 SD0689 0.571 0.870 SD0690 0.697 0.946 SD0691 0.616 0.840 SD0692 0.644 0.850 SD0693 0.781 0.733 SD0694 1.022 0.902 SD0695 0.458 0.448 SD0696 0.500 0.455 SD0697 0.454 0.444 SD0698 0.497 0.467 SD0699 0.369 0.416 SD0700 0.622 0.552 SD0701 0.542 0.528 SD0702 0.301 0.423 SD0703 0.376 0.367 SD0704 0.373 0.334 SD0705 0.315 0.347 SD0706 0.339 0.351 SD0707 0.245 0.263 SD0708 0.572 0.703 SD0709 0.313 0.484 SD0710 0.297 0.431 SD0711 0.284 0.397 SD0712 0.300 0.471 SD0713 0.297 0.417 SD0714 0.300 0.438 SD0715 0.280 0.430

Example 5. In Vivo Analysis of RNAi Agent Efficacy in Transiently Transgenic and Transgenic Mice

A) Administration and Sample Collection.

In order to evaluate the efficacy of LPA RNAi agents in vivo, transiently transgenic mice were used. At least 30 days prior to cholesterol-conjugated LPA RNAi agent administration, wild-type mice were injected by hydrodynamic tail vein injection with a plasmid containing the SEAP gene under the control of the mouse albumin promoter. LPA gene target sequences were cloned in the 3′ UTR of the plasmid. These mice are noted as SEAP-LPA HTV mice. Cholesterol-conjugated LPA RNAi agents were administered to mice using MLP delivery polymer on day 1 (WO 2012/083185, incorporated herein by reference; melittin was synthesized and modified with CDM-NAG to yield MLP delivery polymer as described therein). Each mouse received an intravenous (IV) injection into the tail vein of 200-250 μL solution containing a dose of LPA RNAi agent+MLP delivery polymer (1:1 w/w RNAi agent: MLP delivery polymer in most cases). In some experiments, LPA RNAi agents were directly conjugated to a delivery polymer. Polymer conjugated LPA RNAi agents were similarly injected into tail vein. The indicated LPA RNAi agent (Table 8B) was conjugated to a polyacrylate polymer, ARF1164-106A-5, having 54.4% ethoxy ethyl amino acrylate (EEAA) amine monomers and 45.6% propyl acrylate propyl monomers (MW 41962 g/mol, polymer synthesized as described in WO 2013/158141) and masked with 3×ACit-NAG, 6×ACit-PEG (polymer masked as described in WO 2012/092373 and PCT/US16/34512). Control serum (pre-treatment) samples were taken from the mice pre-injection on days −4, or −1. Post injection serum samples were taken from the mice days 4, 8, 15, 22, 29, 36, and 43. For some mice, samples were collected on day 3 or day 5, instead of day 4.

In additional experiments, LPA RNAi agents were evaluated in vivo using transiently transgenic mice expressing full length LPA. At least 30 days prior to cholesterol-targeted LPA RNAi agent administration, immune compromised (Nod.scid) mice were injected by hydrodynamic tail vein injection with a minicircle containing the LPA cDNA under the control of the mouse albumin promoter. These mice are noted as LPA mc HTV mice. Either cholesterol-targeted or NAG (also termed GalNAc)-conjugated LPA RNAi agents were administered to mice on day 1. For Cholesterol-targeted RNAi agents, each mouse received an intravenous (IV) injection into the tail vein of 200-250 μL solution containing a dose of RNAi agent+MLP delivery polymer (1:1 w/w RNAi agent:MLP delivery polymer). For NAG conjugated LPA RNAi agents, mice received a subcutaneous (SC) injection into the loose skin on the back between the shoulders of 300 μl solution containing a dose of the RNAi agent in buffered saline. For some sample, the LPA RNAi agent was administered either with or without MLP delivery peptide. RNAi agents delivered with MLP delivery peptide were administered by intravenous (IV) injection into the tail vein of 200-250 μL solution containing a dose of RNAi agent+MLP delivery polymer (1:2 w/w RNAi agent: MLP delivery polymer in most cases). Control serum (pre-treatment) samples were taken from the mice pre-injection on days −4, or −1. Post injection serum samples were taken from the mice days 4, 8, 15, 22, 29, 36, and 43. For some mice, samples were collected on day 3 or day 5, instead of day 4.

In further experiments, LPA RNAi agents were administered to apo(a) and Lp(a) transgenic mice (Frazer K A et al 1995, Nature Genetics 9:424-431). This mouse expresses human apo(a) from a YAC containing the full LPA gene (encoding apo(a) protein) with additional sequences both 5′ and 3′. Lp(a) mice were bred by crossing apo(a) YAC-containing mice to human apoB-100 expressing mice (Callow M J et al 1994, PNAS 91:2130-2134). Cholesterol-targeted RNAi agents and NAG conjugated RNAi agents were administered as described above. Control serum (pre-treatment) samples were taken from the mice pre-injection on day −1. Post injection serum samples were taken from the mice days 4, 8, 15, 22, 29, 36, 43, 50, 57 and 64.

B) LPA expression knockdown analyses. For SEAP-LPA HTV mice, SEAP protein levels in serum were monitored by assaying serum from the mice using Phospha-Light™, a chemiluminescent reporter gene assay system (Life Technologies). For normalization, SEAP level for each animal at a given time point was divided by the pre-treatment level of expression in that animal to determine the ratio of expression “normalized to pre-treatment”. Expression at a specific time point was then averaged amongst individuals within the group.

For LPA mc HTV mice and transgenic mice, human apo(a) protein levels in serum were monitored by assaying serum from mice using an ELISA for apo(a) (Abcam). For normalization, apo(a) level for each animal at a time point was divided by the pre-treatment level of expression in that animal (in this case at day 1) to determine the ratio of expression “normalized to day 1”. Expression at a specific time point was then normalized to the saline control group by dividing the “normalized to day 1” ratio for an individual animal by the mean “normalized to day 1” ratio of all mice in the saline control group. This resulted in expression for each time point normalized to that in the control group.

Lp(a) levels were determined on a Cobas Integra 400 (Roche Diagnostics) according to the manufacturer's recommendations. For normalization, apo(a) level for each animal at a time point was divided by the pre-treatment level of expression in that animal (in this case at day 1) to determine the ratio of expression “normalized to day 1”. Expression at a specific time point was then normalized to the saline control group by dividing the “normalized to day 1” ratio for an individual animal by the mean “normalized to day 1” ratio of all mice in the saline control group. This resulted in expression for each time point normalized to that in the control group.

TABLE 8A Relative LPA levels in mouse following intravenous administration of cholesterol-conjugated LPA RNAi agents + MLP delivery polymer. LPA RNAi MLP Duplex ID agent (mg/kg) (mg/kg) Relative LPA AD01184 2 2 0.20 AD01187 2 2 0.18 AD01190 2 2 0.17 AD01193 2 2 0.22 AD01196 2 2 0.02 AD01197 2 2 0.065 AD01198 2 2 0.051 AD01199 2 2 0.070 AD01200 2 2 0.094 AD01201 2 2 0.029 AD01202 8 8 0.14 AD01205 2 2 0.21 AD01206 2 2 0.37 AD01207 2 2 0.19 AD01208 2 2 0.35 AD01209 2 2 0.16 AD01210 2 2 0.18 AD01211 2 2 0.38 AD01212 2 2 0.26 AD01213 2 2 0.30 AD02662 2 2 0.0010 AD02663 2 2 0.010 AD02664 2 2 0.0010

TABLE 8B Relative LPA levels in mouse following intravenous administration of delivery polymer-conjugated LPA RNAi agents. Duplex LPA RNAi agent ID (mg/kg) Relative LPA AD01462 0.5 0.38 AD01463 0.5 0.41 AD01466 0.5 0.33 AD01467 0.5 0.46

TABLE 8C Relative LPA levels in mouse following subcutaneous administration of NAG-conjugated LPA RNAi agents. LPA RNAi agent Duplex ID (mg/kg) Relative LPA AD01529 10 0.068 AD01530 10 0.43 AD01531 10 0.62 AD01532 10 0.18 AD01533 10 0.30 AD01534 10 0.44 AD01765 10 0.14 AD01766 10 0.52 AD01767 10 0.51 AD01768 10 0.15 AD01769 10 0.56 AD01770 10 0.29 AD01772 10 0.25 AD01773 10 0.28 AD01774 10 0.24 AD01780 10 0.34 AD01804 10 0.68 AD01976 10 0.27 AD01977 10 0.27 AD01978 10 0.53 AD01979 10 0.044 AD01980 10 0.087 AD01981 10 0.074 AD01982 10 0.066 AD01983 10 0.078 AD01984 10 0.036 AD01985 10 0.0070 AD01986 10 0.019 AD01987 10 0.019 AD01988 10 0.042 AD01989 10 0.053 AD01990 10 0.017 AD02001 10 0.021 AD02003 10 0.050 AD02004 10 0.050 AD02005 10 0.040 AD02006 10 0.11 AD02007 10 0.21 AD02008 10 0.080 AD02009 10 0.090 AD02010 10 0.16 AD02011 10 0.070 AD02435 10 0.038 AD02436 10 0.027 AD02437 10 0.052 AD02438 10 0.063 AD02439 10 0.073 AD02440 10 0.13 AD02545 10 0.079 AD02546 10 0.045 AD02547 10 0.055 AD02548 10 0.13 AD02549 10 0.071 AD02550 10 0.039 AD02551 10 0.057 AD02552 10 0.033 AD02553 10 0.14 AD02554 10 0.14 AD02555 10 0.18 AD02556 10 0.10 AD02557 10 0.10 AD02558 10 0.071 AD02559 10 0.039 AD02560 10 0.058 AD02561 10 0.12 AD02609 3 0.59 AD02610 3 0.36 AD02611 3 0.35 AD02612 3 0.37 AD02613 3 0.24 AD02614 3 0.24 AD02615 3 0.14 AD02616 3 0.25 AD02617 3 0.090 AD02618 3 0.11 AD02619 3 0.020 AD02620 3 0.11 AD02682 10 0.11 AD02683 10 0.14 AD02684 10 0.79 AD02685 10 0.78 AD02686 10 0.19 AD02687 10 0.27 AD02696 3 0.050 AD02710 3 0.040 AD02711 3 0.040 AD02712 3 0.49 AD02713 3 0.040 AD02714 3 0.040 AD02715 3 0.070 AD02716 3 0.080 AD02717 3 0.12 AD02745 3 0.25 AD02746 3 0.22 AD02747 3 0.081 AD02748 3 0.17 AD02749 3 0.17 AD02750 3 0.066 AD02751 3 0.070 AD02752 3 0.044 AD02753 3 0.071 AD02819 1 0.022 AD02820 1 0.042 AD02821 1 0.038 AD02825 3 0.050 AD02826 3 0.050 AD02827 3 0.050 AD02828 3 0.050 AD02829 3 0.040 AD02830 3 0.040 AD02831 3 0.030 AD02832 3 0.030 AD02841 3 0.061 AD02842 3 0.16 AD02843 3 0.10 AD02844 3 0.11 AD02845 3 0.22 AD02846 3 0.16 AD02847 3 0.066 AD02848 3 0.055 AD02849 3 0.083 AD02850 3 0.042 AD02851 3 0.063 AD02852 3 0.11 AD02907 10 0.10 AD02908 10 0.11 AD02909 10 0.049 AD02910 10 0.23 AD02911 10 0.20 AD02912 10 0.10 AD02913 10 0.070 AD02914 10 0.050 AD02915 10 0.10 AD02916 10 0.090 AD02917 10 0.060 AD02918 10 0.020 AD02919 10 0.030 AD02920 10 0.050 AD02921 10 0.040 AD02922 10 0.080 AD02923 10 0.040 AD02924 10 0.050 AD02925 10 0.030 AD02926 10 0.17 AD02927 10 0.31 AD02928 10 0.081 AD02929 10 0.065 AD02930 10 0.15 AD02931 10 0.13 AD02932 10 0.11 AD03049 3 0.20 AD03050 3 0.087 AD03051 3 0.070 AD03052 3 0.080 AD03053 3 0.23 AD03054 3 0.050 AD03058 3 0.27 AD03059 3 0.22 AD03060 3 0.31 AD03061 3 0.16 AD03062 3 0.20 AD03063 3 0.13 AD03064 3 0.21 AD03065 3 0.085 AD03066 3 0.10 AD03067 3 0.094 AD03068 3 0.17 AD03069 3 0.077 AD03070 3 0.36 AD03071 3 0.043 AD03072 3 0.031 AD03073 3 0.019 AD03074 3 0.016 AD03075 3 0.062 AD03114 1 0.33 AD03115 1 0.30 AD03116 1 0.21 AD03117 1 0.14 AD03118 1 0.30 AD03119 1 0.10 AD03120 1 0.080 AD03121 1 0.14 AD03122 1 0.14 AD03123 1 0.34 AD03156 1 0.084 AD03157 1 0.016 AD03158 1 0.037 AD03159 1 0.63 AD03272 1 0.13 AD03273 1 0.20 AD03274 1 0.21 AD03275 1 0.15 AD03276 1 0.11 AD03277 1 0.13 AD03278 1 0.13 AD03279 1 0.21 AD03341 1 0.13 AD03421 1 0.29 AD03430 1 0.12 AD03432 1 0.16 AD03434 1 0.11 AD03436 1 0.21 AD03438 1 0.25 AD03440 1 0.21 AD03460 1 0.090 AD03462 1 0.40 AD03495 1 0.28 AD03536 1 0.14 AD03538 0.5 0.26 AD03539 0.5 0.21 AD03540 1 0.15 AD03541 0.5 0.10 AD03542 1 0.94 AD03547 1 0.19 AD03548 1 0.73 AD03549 1 0.29 AD03573 1 0.15 AD03574 1 0.15 AD03575 1 0.13 AD03576 1 0.18 AD03577 0.5 0.18 AD03578 0.5 0.38 AD03579 0.5 0.53 AD03603 1 0.083 AD03604 1 0.091 AD03605 1 0.19 AD03608 1 0.18 AD03609 1 0.16 AD03610 1 0.23 AD03611 1 0.40 AD03612 1 0.21 AD03629 1 0.11 AD03668 1 0.070 AD03705 0.5 0.11 AD03707 0.5 0.11 AD03720 0.5 0.14 AD03721 0.5 0.094 AD03722 0.5 0.19 AD03723 0.5 0.10 AD03765 1 0.080 AD03771 1 0.10 AD03801 1 0.15 AD03802 1 0.18 AD03844 1 0.17 AD03845 1 0.25 AD03848 1 0.10 AD03850 1 0.052 AD03851 1 0.076 AD03852 1 0.13 AD03853 1 0.081 AD03854 1 0.21 AD03856 1 0.32 AD03859 1 0.15 AD03862 1 0.12 AD03863 1 0.12 AD03921 1 0.17 AD03922 1 0.057 AD03923 1 0.066 AD03924 1 0.14 AD03931 1 0.34 AD03932 1 0.15 AD03933 1 0.34 AD03424 1 0.15 AD03425 1 0.21 AD03426 1 0.21 AD03427 1 0.19 AD03428 1 0.18 AD03760 0.5 0.21 AD03762 0.5 0.17 AD03763 0.5 0.21 AD03764 0.5 0.28 AD03766 0.5 0.065 AD03847 1 0.15 AD04110 1 0.070

Example 6. In Vivo Screening of LPA RNAi Agents and Time Course of SEAP Knockdown

Cholesterol-conjugated LPA RNAi agents were administered to transiently transgenic mice as described above. Each mouse received a single intravenous (IV) dose of 8 mg/kg of LPA RNAi agent with 8 mg/kg of MLP delivery polymer. SEAP protein levels in serum were monitored for up to 36 days. Knockdown levels and duration of response are shown in Table 9. A decrease in SEAP serum protein level of greater than 85% was obtained following administration of all LPA RNAi agents tested; with all but two LPA RNAi agents tested showing greater than 99.4% knockdown. AD01196 and AD01199 showed >95% knockdown at day 36.

Example 7. In Vivo Screening LPA RNAi Agents and Time Course of LPA Knockdown at Lower LPA RNAi Agent Doses

Cholesterol-conjugated LPA RNAi agents were administered to transiently transgenic mice as described above. Each mouse received a single intravenous (IV) dose of 2 mg/kg of LPA RNAi agent with 2 mg/kg of MLP delivery polymer. SEAP protein levels in serum were monitored for up to 43 days (Table 10).

Example 8. In Vivo Testing of LPA RNAi Agents in Apo(a) Transgenic (Tg) Mice

AD01196 was administered to mice as described above. Each mouse received a single intravenous (IV) dose of either 2 mg/kg of LPA RNAi agent with 2 mg/kg of MLP delivery polymer or saline. Human apo(a) (apo(a)) levels in serum were monitored for up to 64 days (Table 11). At day 15, animals in the saline group received a single IV dose of 2 mg/kg of a control mouse Factor VII (F7) RNAi agent with 2 mg/kg of MLP delivery polymer. At day 22, F7 levels were measured in all animals. F7 activity was knocked down by 99% 7 days post dosing, with no effect on serum apo(a) levels. AD01196 showed >3 log 10 knockdown of apo(a) levels at nadir, with >80% knockdown observed after 3 weeks (Table 11).

TABLE 9 Serum SEAP protein levels in SEAP-LPA HTV mice following administration of 8 mg/kg chol-RNAi agents with 8 mg/kg MLP delivery peptide. SEAP levels were normalized to day −1 and saline control. Day −1 Day 4 Day 8 Day 15 Day 22 Day 29 Day 36 Treatment Ave SD Ave SD Ave SD Ave SD Ave SD Ave SD Ave SD Saline 1.00 0.24 1.00 0.34 1.00 0.13 1.00 0.33 1.00 0.09 1.00 0.18 1.00 0.44 AD01184 1.00 0.39 0.27 0.10 0.15 0.06 0.01 0.00 0.07 0.04 0.43 0.39 0.98 0.73 AD01187 1.00 0.53 0.24 0.15 0.13 0.10 0.00 0.00 0.01 0.01 0.08 0.06 0.56 0.47 AD01190 1.00 0.77 0.26 0.20 0.14 0.11 0.00 0.00 0.00 0.00 0.00 0.00 0.02 0.01 AD01193 1.00 0.99 0.25 0.26 0.15 0.17 0.01 0.01 0.00 0.00 0.01 0.01 0.02 0.01 AD01196 1.00 0.59 0.24 0.13 0.14 0.08 0.00 0.00 0.00 0.00 0.01 0.01 0.04 0.03 AD01199 1.00 0.52 0.23 0.15 0.13 0.10 0.00 0.00 0.00 0.00 0.01 0.00 0.04 0.02 AD01202 1.00 0.93 0.25 0.24 0.17 0.16 0.14 0.12 0.56 0.55 0.78 0.66 2.09 2.00

TABLE 10 Serum SEAP protein levels in SEAP-LPA HTV mice following administration of 2 mg/kg chol-RNAi agents with 2 mg/kg MLP delivery peptide. SEAP levels were normalized to day −1 and saline control. Day −4 Day 4 Day 9 Day 15 Day 22 Day 29 Day 36 Day 43 Treatment Ave. SD Ave. SD Ave. SD Ave. SD Ave. SD Ave. SD Ave. SD Ave. SD Saline 1.00 0.00 1.00 0.72 1.00 0.72 1.00 0.71 1.00 0.43 1.00 0.79 1.00 0.48 1.00 0.54 AD01196 1.00 0.00 0.22 0.08 0.05 0.05 0.02 0.01 0.13 0.04 0.36 0.12 0.69 0.08 1.39 0.91 AD01199 1.00 0.00 0.27 0.28 0.07 0.06 0.17 0.17 0.59 0.51 0.74 0.74 0.83 0.82 1.01 0.58 AD01205 1.00 0.00 0.21 0.13 0.31 0.23 0.45 0.21 1.33 0.68 1.11 0.82 1.55 1.30 1.79 1.09 AD01208 1.00 0.00 0.43 0.20 0.35 0.15 0.68 0.19 1.45 0.44 1.32 0.26 1.39 0.52 0.99 0.12 AD01211 1.00 0.00 0.38 0.14 0.53 0.20 0.94 0.38 1.96 0.93 1.05 0.27 1.44 0.38 0.93 0.28 AD01184 1.00 0.00 0.26 0.07 0.20 0.05 0.61 0.17 1.28 0.14 1.21 0.51 1.39 0.80 ND ND AD01187 1.00 0.00 0.37 0.18 0.09 0.07 0.18 0.17 0.86 0.84 0.77 0.33 1.80 0.36 ND ND AD01190 1.00 0.00 0.26 0.08 0.17 0.07 0.36 0.13 1.16 0.37 1.39 0.69 1.96 1.64 ND ND AD01193 1.00 0.00 0.39 0.27 0.22 0.33 0.32 0.37 0.67 0.58 0.84 0.46 1.27 0.23 ND ND

TABLE 11 Serum apo(a) protein levels in apo(a) Tg mice following administration of 2 mg/kg cholesterol-conjugated LPA RNAi agent with 2 mg/kg MLP delivery polymer. Apo(a) levels were normalized to day −1 and saline control. Day −1 Day 4 Day 8 Day 15 Day 22 Treatment Ave SD Ave SD Ave SD Ave SD Ave SD Saline 1.00 0.00 1.00 0.06 1.00 0.27 1.00 0.06 1.00 0.17 AD01196 1.00 0.00 0.00 0.00 0.00 0.00 0.01 0.00 0.15 0.08 Day 29 Day 36 Day 43 Day 50 Ave SD Ave SD Ave SD Ave SD Saline 1.00 0.12 1.00 0.04 1.00 0.26 1.00 0.24 AD01196 0.40 0.23 0.74 0.61 0.75 0.67 0.77 0.52

Example 9. Apolipoprotein (a) (Apo(a)) Knockdown in Non-Human Primates Following LPA RNAi Agent Delivery by MLP Delivery Polymer

MLP delivery polymer and LPA RNAi agent were made and combined in a pharmaceutically acceptable buffer as described above. On day 1, two cynomolgus macaque (Macaca fascicularis) primates (both male, 5.0 kg and 8.15 kg, respectively) were injected with 2 mg/kg AD01196+2 mg/kg MLP delivery polymer. For each injection, the LPA RNAi agent+MLP delivery polymer (2 ml/kg) was injected into the saphenous vein using a 22 to 25 gauge intravenous catheter. At the indicated time points (indicated in Table 12), blood samples were drawn and analyzed for apo(a) levels, lipid levels and toxicity markers. Blood was collected from the femoral vein and primates were fasted overnight before all blood collections. Blood tests for blood urea nitrogen (BUN), alanine transaminase (ALT), aspartate aminotransferase (AST), creatinine, total cholesterol (TC) and triglycerides (TG) were performed on an automated chemistry analyzer at Meriter laboratories. Blood tests for Lipoprotein (a) (Lp(a)) and Low density lipoprotein (LDL) were measured on an automated chemistry analyzer. Serum apo(a) levels were measured by ELISA. Significant knockdown of apo(a) was observed with an average maximum knockdown of 94.5% observed at day 22. Average maximum knockdown of Lp(a) was 91.5% observed at day 15 (FIG. 3). No dose-related toxicity was observed in treated animals.

TABLE 12 Serum apo(a) protein, Lipoprotein(a) (mg/dL), Low density Lipoprotein (LDL), Total cholesterol, and triglyceride levels in cynomolgus macaque (Macaca fascicularis) primates following administration of 2 mg/kg AD01196 with 2 mg/kg MLP delivery polymer. Apo(a) levels were normalized to predose. Low Density Serum apo(a) Lipoprotein(a) Lipoprotein Total protein levels calculated Cholesterol Triglycerides levels (mg/dL) (mg/dL) (mg/dL) (mg/dL) animal animal animal animal animal animal animal animal animal animal day 1 2 1 2 1 2 1 2 1 2 pre 1.00 1.00 77.1 126.7 48.4 84.7 95 149 41 36 3 0.47 0.55 46.0 65.0 53.6 83.5 93 143 33 28 8 0.12 0.15 9.3 16.5 53.4 75.9 101 147 36 30 15 0.10 0.10 5.0 7.3 49.8 60.9 106 136 79 34 22 0.05 0.06 7.9 10.3 47.5 63.9 97 136 34 36 29 0.08 0.11 13.4 27.0 55.7 47.5 101 116 20 36 36 0.15 0.25 22.2 50.6 56.8 73.1 — — — — 43 0.19 0.23 31.4 45.5 53.8 55.7 103 138 29 39 50 0.27 0.29 46.1 67.3 52.3 70.9 — — — — 57 0.27 0.3 52.7 69.7 52.1 78.6 104 157 34 39 64 0.33 0.31 68.4 73.7 52.4 75.8 — — — — 71 0.50 0.4 76.8 78.6 62.4 75.0 104 149 43 47 85 0.31 0.34 63.1 75.4 50.3 68.8 102 145 41 49 99 0.27 0.29 67.9 78.8 58.7 72.5 102 150 42 52 120 0.36 0.37 91.7 119.4 53.4 79.8 100 154 43 51

TABLE 13 Urea Nitrogen, Creatinine, Alanine transaminase, and Aspartate aminotransferase levels in cynomolgus macaque (Macaca fascicularis) primates following administration of 2 mg/kg AD01196 with 2 mg/kg MLP delivery polymer. Blood Urea Alanine Aspartate Nitrogen Creatinine transaminase aminotransferase (mg/dL) (mg/dL) (U/L) (U/L) day animal 1 animal 2 animal 1 animal 2 animal 1 animal 2 animal 1 animal 2 predose 16 16 0.79 0.70 37 32 32 33 3 11 14 0.70 0.61 40 42 33 35 8 14 13 0.78 0.58 33 38 25 31 15 15 15 0.67 0.59 51 35 47 32 22 15 15 0.8 0.55 47 35 29 30 29 12 12 0.61 0.59 30 31 23 36 36 — — — — — — — — 43 12 15 0.64 0.58 29 29 25 30 50 — — — — — — — — 57 14 15 0.72 0.64 32 35 28 31 64 — — — — — — — — 71 14 15 0.73 0.69 36 35 29 33 85 14 15 0.60 0.70 126 41 51 40 99 15 18 0.66 0.68 151 40 44 37 120 14 19 0.72 0.60 37 51 28 47

Example 10. In Vivo Screening of NAG-Conjugated LPA RNAi Agents and Time Course of Knockdown

NAG-conjugated LPA RNAi agents were administered to transiently transgenic mice as described above. Each mouse received either single intravenous (IV) dose of 2 mg/kg of LPA RNAi agent with 1 mg/kg of MLP delivery polymer, or a single subcutaneous (SC) dose of 10 mg/kg of the NAG-conjugated LPA RNAi agent. SEAP protein levels in serum were monitored for up to 22 days. Knockdown levels and duration of response are shown in Tables 14-15. AD01529, AD01532 and AD01533 showed >85% knockdown of SEAP levels following IV administration with MLP deliver polymer, and >60% maximum knockdown of SEAP levels following SC administration of the NAG-conjugated LPA RNAi agent alone.

TABLE 14 Serum SEAP protein levels in SEAP-LPA HTV mice following SC administration of 10 mg/kg NAG-conjugated LPA RNAi agents. SEAP levels were normalized to day −1 and saline control. Day −1 Day 4 Day 8 Day 15 Day 22 Treatment Ave SD Ave SD Ave SD Ave SD Ave SD Saline 1.00 0.00 1.00 0.14 1.00 0.14 1.00 0.66 1.00 0.27 AD01529 1.00 0.00 0.45 0.07 0.36 0.03 0.60 0.08 0.90 0.37 AD01530 1.00 0.00 0.46 0.15 0.43 0.10 0.79 0.26 0.79 0.32 AD01531 1.00 0.00 0.64 0.13 0.62 0.06 0.99 0.28 1.17 0.29 AD01532 1.00 0.00 0.41 0.12 0.37 0.11 0.99 0.34 1.33 0.11 AD01533 1.00 0.00 0.40 0.03 0.22 0.08 0.37 0.15 0.63 0.13 AD01534 1.00 0.00 0.65 0.19 0.44 0.19 0.74 0.30 1.17 0.55

TABLE 15 Serum SEAP protein levels in SEAP-LPA HTV mice following IV administration of 1 mg/kg NAG-conjugated LPA RNAi agents + 2 mg/kg MLP delivery polymer. SEAP levels were normalized to day −1 and saline control. Day −1 Day 4 Day 8 Day 15 Day 22 Treatment Ave SD Ave SD Ave SD Ave SD Ave SD Saline 1.00 0.00 1.00 0.33 1.00 0.46 1.00 0.21 1.00 0.39 F7 Control 1.00 0.00 0.61 0.05 0.71 0.45 1.25 0.44 1.05 0.49 AD01529 1.00 0.00 0.25 0.04 0.15 0.08 0.47 0.24 0.81 0.40 AD01530 1.00 0.00 0.26 0.06 0.28 0.19 0.78 0.60 1.06 0.63 AD01531 1.00 0.00 0.22 0.07 0.26 0.06 0.72 0.21 1.04 0.12 AD01532 1.00 0.00 0.18 0.05 0.06 0.03 0.13 0.08 0.29 0.18 AD01533 1.00 0.00 0.21 0.04 0.13 0.06 0.32 0.15 0.67 0.28 AD01534 1.00 0.00 0.17 0.04 0.22 0.06 0.66 0.24 0.94 0.24

Example 11. In Vivo Screening of Modified NAG-Conjugated LPA RNAi Agents and Time Course of Knockdown

The indicated NAG-conjugated LPA RNAi agents were administered to SEAP-LPA HTV mice as described above. Each mouse received a single subcutaneous (SC) dose of 10 mg/kg of the NAG-conjugated LPA RNAi agent. SEAP protein levels in serum were monitored for up to 22 days. Knockdown levels and duration of response are shown in Tables 16-17. AD01765 and AD01768 showed 89% knockdown activity.

TABLE 16 Serum SEAP protein levels in SEAP-LPA HTV mice following SC administration of 10 mg/kg NAG-conjugated LPA RNAi agent. SEAP levels were normalized to day −1 and saline control. Day −1 Day 3 Day 8 Day 15 Day 22 Treatment Ave SD Ave SD Ave SD Ave SD Ave SD Saline 1.00 0.00 1.00 0.16 1.00 0.16 1.00 0.28 1.00 0.24 AD01533 1.00 0.00 0.41 0.08 0.22 0.02 0.47 0.20 0.66 0.29 AD01772 1.00 0.00 0.46 0.13 0.18 0.00 0.34 0.09 0.61 0.14 AD01773 1.00 0.00 0.47 0.08 0.20 0.08 0.45 0.15 0.83 0.12 AD01774 1.00 0.00 0.49 0.09 0.18 0.03 0.44 0.13 0.68 0.08 AD01780 1.00 0.00 0.52 0.13 0.25 0.09 0.44 0.26 0.65 0.37

TABLE 17 Serum SEAP protein levels in SEAP-LPA HTV mice following SC administration of 10 mg/kg NAG-conjugated LPA RNAi agent. SEAP levels were normalized to day −1 and saline control. Day −1 Day 3 Day 8 Day 15 Day 22 Treatment Ave SD Ave SD Ave SD Ave SD Ave SD Saline 1.00 0.00 1.00 0.27 1.00 0.73 1.00 0.87 1.00 0.80 AD01532 1.00 0.00 0.42 0.19 0.35 0.21 0.85 0.25 1.27 0.57 AD01765 1.00 0.00 0.35 0.02 0.11 0.08 0.25 0.14 0.47 0.19 AD01766 1.00 0.00 0.52 0.10 0.36 0.09 1.05 0.13 1.15 0.08 AD01767 1.00 0.00 0.49 0.03 0.44 0.05 1.43 0.23 1.33 0.71 AD01768 1.00 0.00 0.34 0.15 0.11 0.07 0.39 0.13 0.76 0.19 AD01769 1.00 0.00 0.54 0.17 0.46 0.14 1.32 0.12 1.38 0.37 AD01770 1.00 0.00 0.41 0.07 0.20 0.10 0.80 0.52 1.04 0.67

Example 12. In Vivo Testing of NAG-Conjugated LPA RNAi Agents in Apo(a) Tg Mice

NAG-conjugated LPA RNAi agents were administered to apo(a) Tg mice as described above. Each mouse received a single subcutaneous (SC) dose of either 10 mg/kg of LPA RNAi agent or saline. Human apo(a) (apo(a)) levels in serum were monitored for up to days (Table 18). AD01765 showed the largest knockdown of apo(a) levels at day 8 with 96% knockdown, and >74% knockdown observed 3 weeks after dosing.

TABLE 18 Serum apo(a) protein levels in apo(a) Tg mice following SC administration of 10 mg/kg NAG-conjugated LPA RNAi agent. Apo(a) levels were normalized to day −1 and saline control. Day −1 Day 4 Day 8 Day 15 Day 22 Treatment Ave SD Ave SD Ave SD Ave SD Ave SD Saline 1.00 0.00 1.00 0.10 1.00 0.16 1.00 0.42 1.00 0.21 AD01532 1.00 0.00 0.12 0.05 0.22 0.08 0.76 0.30 0.56 0.28 AD01765 1.00 0.00 0.09 0.03 0.04 0.02 0.14 0.02 0.26 0.04 AD01768 1.00 0.00 0.11 0.05 0.09 0.05 0.26 0.12 0.38 0.08

Example 13. In Vivo Testing of NAG-Conjugates LPA RNAi Agents in LPA Mc HTV Mice

Indicated NAG-conjugated LPA RNAi agents were administered to LPA mc HTV mice as described above. Each mouse received a single subcutaneous (SC) dose of either 10 mg/kg of LPA RNAi agent or saline. Human apo(a) (apo(a)) levels in serum were analyzed at day 4 (Table 19). AD02001, AD01765 and AD01768 showed >90% knockdown at day 4.

TABLE 19 Serum apo(a) protein levels in LPA mc HTV mice following SC administration of 10 mg/kg NAG-conjugated LPA RNAi agent. Apo(a) levels were normalized to day −1 and saline control. Prebleed Day 4 Treatment Ave SD Ave SD saline 1.00 0.00 1.00 0.12 AD01765 1.00 0.00 0.05 0.02 AD01768 1.00 0.00 0.07 0.01 AD01804 1.00 0.00 0.68 0.16 AD02001 1.00 0.00 0.06 0.03

Example 14. Apolipoprotein (a) (Apo(a)) Knockdown in Non-Human Primates Following LPA RNAi Agent Delivery by MLP Delivery Polymer

MLP delivery polymer and LPA RNAi agent were made and combined in a pharmaceutically acceptable buffer. On day 1 and day 71, two cynomolgus macaque (Macaca fascicularis) primates were injected with either 4 mg/kg AD01196+4 mg/kg MLP delivery polymer or 6 mg/kg AD01196+6 mg/kg MLP delivery polymer. For each injection, the LPA RNAi agent+MLP delivery polymer was injected into the saphenous vein using a 22 to 25 gauge intravenous catheter. At the indicated time points (FIG. 4), blood samples were drawn and analyzed for apo(a) levels, lipid levels and toxicity markers as previously described. Significant knockdown of apo(a) was observed after the first dose with an average maximum knockdown of 96% for 4 mg/kg dose on day 15, and 96% for 6 mg/kg dose observed at day 15. Average maximum knockdown of Lp(a) after the first dose was 98.5% for 4 mg/kg dose on day 29, and 98.5% for 6 mg/kg dose on day 22. No dose-related toxicity was observed in treated animals.

Example 15. In Vivo Testing of NAG-Conjugated LPA RNAi Agents in Lp(a) Tg Mice-Dose Response

NAG-conjugated LPA RNAi agents were administered to Lp(a) Tg mice as described above. Each mouse received a single subcutaneous (SC) dose of either LPA RNAi agent at 0.5 mg/kg or 2 mg/kg dose levels or saline. Lp(a) levels in serum were monitored up to day 43 (FIG. 1, FIG. 2). All LPA RNAi agents showed dose-response with the higher doses showing greater knockdown with nadir between days 15 and 22.

Example 16. Apolipoprotein (a) (Apo(a)) Knockdown in Non-Human Primates Following Apo(a) Specific LPA RNAi Agent Molecule Delivery

LPA RNAi agent was prepared in a pharmaceutically acceptable buffer as described herein for subcutaneous (SC) injection. On days 1, 7, and 15, two cynomolgus macaque (Macaca fascicularis) primates were injected subcutaneously with 3 mg/kg of AD02713, AD02819, AD02820, or AD02821. In addition, AD02819-treated monkeys were dosed again with 3 mg/kg of AD02819 on day 57 and day 85. Blood samples were drawn and analyzed for apo(a) levels, lipid levels and toxicity markers as previously described. Significant knockdown of Lp(a) was observed with an average maximum knockdown of 89% observed at day 43 for AD02713, 87% observed on day 36 for AD02819, 79% observed on day 36 for AD02820, and 95% observed on day 29 for AD02821 (FIG. 5). No dose-related toxicity was observed in treated animals over the time of the experiment.

Example 17. Apolipoprotein (a) (Apo(a)) Knockdown in Non-Human Primates Following LPA RNAi Agent Delivery

LPA RNAi agent was prepared in a pharmaceutically acceptable buffer as described herein for subcutaneous (SC) injection. On day 1, two cynomolgus macaque (Macaca fascicularis) primates were injected subcutaneously with 3 mg/kg of AD03272, AD03462, AD03549, AD03547, AD03668, AD03460, or AD03536. In addition, AD03460 and AD03536-treated monkeys were dosed again with 1 mg/kg of the respective LPA RNAi agent on day 48. Blood samples were drawn and analyzed for apo(a) levels, lipid levels and toxicity markers as previously described. Significant knockdown of Lp(a) was observed with an average maximum knockdown of 62% for AD03272 on day 15, 28% for AD03462 on day 15, 47% for AD03549 on day 29, 44% for AD03547 on day 15, 53% for AD03668 on day 22, 79% for AD03460 on day 29, and 71% for AD03536 on day 22 (FIG. 6). No dose-related toxicity was observed in treated animals over the time of the experiment.

Example 18. Apolipoprotein (a) (Apo(a)) Knockdown in Primate Following Apo(a) Specific LPA RNAi Agent Molecule Delivery

LPA RNAi agent was made and combined in a pharmaceutically acceptable buffer as described above for subcutaneous (SQ) injection. On day 1, cynomolgus macaque (Macaca fascicularis) primates were injected with subcutaneously with saline or 2 mg/kg of AD03460, AD03536, AD03851, AD03853, or AD04110. Blood samples were drawn and analyzed for apo(a) levels, lipid levels and toxicity markers on days 8 and 15 as previously described. Lp(a) levels were normalized to average of three predose values.

TABLE 20 Lipoprotein(a) levels in cynomolgus macaque primates following administration of either saline or 2 mg/kg AD03460, AD03536, AD03851, AD03853 or AD04110. Normalized Lp(a) Normalized Lp(a) Day 8 Day 8 Saline 1.01 ± 0.06 1.15 ± 0.07 AD03460 0.68 ± 0.12 0.40 ± 0.13 AD03536 0.54 ± 0.07 0.21 ± 0.06 AD03581 0.41 ± 0.08 0.18 ± 0.08 AD03583 0.50 ± 0.23 0.27 ± 0.17 AD04110 0.59 ± 0.13 0.43 ± 0.10 

1. An LPA RNA interference (RNAi) agent comprising a sense strand and an antisense strand, wherein said antisense strand comprises the nucleotide sequence of a) nucleotides 2-19 of any of SEQ ID NOs:1-108, or b) any of the antisense strands of Table 1 or Table 2A.
 2. The LPA RNAi agent of claim 1, wherein the sense strand comprises the nucleotide sequence of a) nucleotides 1-19 of any of SEQ ID NOs:190-268, or b) any of the sense strands of Table 1 or Table 2B.
 3. The LPA RNAi agent of claim 1, wherein the antisense strand comprises the nucleotide sequence of any of SEQ ID NO:1246, SEQ ID NO:1242, SEQ ID NO:1244, SEQ ID NO:1248, SEQ ID NO:1250, SEQ ID NO:1252, or SEQ ID NO:1254, SEQ ID NO:1280, SEQ ID NO:1281, SEQ ID NO:1282, OR SEQ ID NO:1283.
 4. The LPA RNAi agent of claim 3, wherein: a) the antisense strand comprises the nucleotide sequence of SEQ ID NO:1246 and the sense strand comprises the nucleotide sequence of SEQ ID NO:1247; b) the antisense strand comprises the nucleotide sequence of SEQ ID NO:1242 and the sense strand comprises the nucleotide sequence of SEQ ID NO:1243; c) the antisense strand comprises the nucleotide sequence of SEQ ID NO:1244 and the sense strand comprises the nucleotide sequence of SEQ ID NO:1245; d) the antisense strand comprises the nucleotide sequence of SEQ ID NO:1248 and the sense strand comprises the nucleotide sequence of SEQ ID NO:1249; e) the antisense strand comprises the nucleotide sequence of SEQ ID NO:1250 and the sense strand comprises the nucleotide sequence of SEQ ID NO:1251; f) the antisense strand comprises the nucleotide sequence of SEQ ID NO:1252 and the sense strand comprises the nucleotide sequence of SEQ ID NO:1253; or g) the antisense strand comprises the nucleotide sequence of SEQ ID NO:1254 and the sense strand comprises the nucleotide sequence of SEQ ID NO:1255; or h) the antisense strand comprises the nucleotide sequence of SEQ ID NO:1280 and the sense strand comprises the nucleotide sequence of SEQ ID NO:1260; OR i) the antisense strand comprises the nucleotide sequence of SEQ ID NO:1281 and the sense strand comprises the nucleotide sequence of SEQ ID NO:1258; or j) the antisense strand comprises the nucleotide sequence of SEQ ID NO:1280 and the sense strand comprises the nucleotide sequence of SEQ ID NO:1284; or k) the antisense strand comprises the nucleotide sequence of SEQ ID NO:1281 and the sense strand comprises the nucleotide sequence of SEQ ID NO:1285; or l) the antisense strand comprises the nucleotide sequence of SEQ ID NO:1282 and the sense strand comprises the nucleotide sequence of SEQ ID NO:1259; or m) the antisense strand comprises the nucleotide sequence of SEQ ID NO:1283 and the sense strand comprises the nucleotide sequence of SEQ ID NO:1249.
 5. The LPA RNAi agent of claim 1, wherein the sense strand and/or the antisense strand further comprises a 3′ and/or 5′ extension of 1-6 nucleotides in length.
 6. The LPA RNAi agent of claim 1 wherein the antisense strand comprises a nucleotide sequence of any of SEQ ID NO:156, SEQ ID NO:164, or SEQ ID NO:188.
 7. The LPA RNAi agent of claim 6, wherein: a) the antisense strand comprises a nucleotide sequence of SEQ ID NO:156. and the sense strand comprises a nucleotide sequence of SEQ ID NO:310, b) the antisense strand comprises a nucleotide sequence of SEQ ID NO:164. and the sense strand comprises a nucleotide sequence of SEQ ID NO:357, c) the antisense strand comprises a nucleotide sequence of SEQ ID NO:188 and the sense strand comprises a nucleotide sequence of SEQ ID NO:384, d) the antisense strand comprises a nucleotide sequence of SEQ ID NO:164 and the sense strand comprises a nucleotide sequence of SEQ ID NO:376, or e) the antisense strand comprises a nucleotide sequence of SEQ ID NO:164 and the sense strand comprises a nucleotide sequence of SEQ ID NO:384.
 8. The LPA RNAi agent of claim 1, wherein the sense strand and/or antisense strand independently comprises one or more modified nucleotides.
 9. The LPA RNAi agent of claim 8, wherein the one or more modified nucleotides are independently selected from the group consisting of: 2′-O-methyl modified nucleotide, nucleotide comprising a 5′-phosphorothioate group, 2′-deoxy-2′-fluoro modified nucleotide, 2′-deoxy-modified nucleotide, locked nucleotide, abasic nucleotide, deoxythymidine, inverted deoxythymidine, 2′-amino-modified nucleotide, 2′-alkyl-modified nucleotide, morpholino nucleotide, and non-natural base comprising nucleotide.
 10. The LPA RNAi agent of claim 1, wherein the LPA RNAi agent comprises one or more phosphorothioate internucleoside linkages.
 11. The LPA RNAi agent of claim 1, wherein the LPA RNAi agent further comprises a targeting group.
 12. The LPA RNAi agent of claim 11, wherein the targeting group comprises an asialoglycoprotein receptor ligand.
 13. The LPA RNAi agent of claim 12, wherein the asialoglycoprotein receptor ligand comprises a galactose cluster.
 14. The LPA RNAi agent of claim 13, wherein the galactose cluster is selected from the group consisting of: (C11-PEG5-NAG5), (C11-PEG5-NAG5), (C6-PEG₄-NAG3), (NAG 3), (NAG4), (NAG3-AA2), (NAG5-Palm), (NAG13), (NAG18), (NAG24), (NAG25), (NAG25)s, (NAG26), (NAG27), (NAG28), (NAG29), (NAG30), (NAG30)s, (NAG31), (NAG13), (NAG31s), (NAG32), (NAG33), (NAG34), (NAG35), (NAG36), and (NAG37).
 15. The LPA RNAi agent of claim 11, wherein the targeting group is conjugated to the sense strand.
 16. The LPA RNAi agent of claim 15, wherein the targeting group is conjugated to the 5′ end of the sense strand.
 17. The LPA RNAi agent of claim 15, wherein the targeting group is conjugated to the 3′ end of the sense strand.
 18. The LPA RNAi agent of claim 1, wherein the LPA RNAi agent further comprises a linking group.
 19. The LPA RNAi agent of claim 1, wherein the LPA RNAi agent comprises one or two overhangs.
 20. The LPA RNAi agent of claim 1, wherein the LPA RNAi agent comprises one or two frayed ends.
 21. The LPA RNAi agent of claim 1, wherein the LPA RNAi agent comprises one or two blunt ends.
 22. The LPA RNAi agent of claim 1, wherein the LPA RNAi agent comprises any of the duplex sequences in Table 3A or Table 3B.
 23. The LPA RNAi agent of claim 22, wherein the LPA RNAi agent comprises AD03460, AD03536, AD03581, AD03583, AD3847, or AD04110,
 24. Use of the LPA RNAi agent of claim 1, for the manufacture of a medicament.
 25. The LPA RNAi agent of claim 1, further comprising one or more additional therapeutics or treatments.
 26. The LPA RNAi agent claim 1, further comprising a pharmaceutically acceptable excipient.
 27. The LPA RNAi agent of claim 1, wherein said LPA RNAi agent is packaged in a kit, container, pack, dispenser, pre-filled syringes, or vials.
 28. A method for inhibiting LPA expression in a cell, tissue, or subject comprising: administering to said subject a therapeutically effective amount of an LPA RNAi agent of claim
 1. 29. The method of claim 28, wherein the composition is administered parenterally.
 30. The method of claim 28, wherein the cell is a hepatocyte.
 31. An LPA RNA interference (RNAi) agent comprising a sense sequence and an antisense sequence, wherein said antisense sequence comprises a nucleotide sequence of nucleotides 1-17, 2-18, 1-19, 2-19, 1-21, 1-23, or 1-26 of any of the antisense sequences of Table 1 or Table 2A. 